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Garbuz M, Ovchinnikova E, Ovchinnikova A, Vinokurova V, Aristarkhova Y, Kuziakova O, Mashurova M, Kumeiko V. Spectrum of Pathogenic Variants of the ATP7B Gene and Genotype-Phenotype Correlation in Eastern Eurasian Patient Cohorts with Wilson's Disease. Biomedicines 2024; 12:2833. [PMID: 39767741 PMCID: PMC11673475 DOI: 10.3390/biomedicines12122833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 12/06/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: Wilson's disease (WD) (OMIM 277900) or hepatolenticular degeneration is an autosomal recessive disorder caused by impaired copper excretion with subsequent accumulation in the liver, brain, and other tissues of the body. The defects in copper metabolism are based on various pathogenic variants of the ATP7B gene encoding copper-transporting P-type ATPase. The aim of this work is to search for pathogenic variants of the ATP7B gene among Eastern Eurasian patient cohorts and to pick correlations between pathogenic variants, gender, age of onset of the disease, and the course of the disease. Methods: The material for the study was the biomaterial of 100 people. The search for mutations was carried out by Sanger sequencing. Multiple alignment of nucleotide sequences and their analysis was performed using the MEGA-X software. To study the genotype-phenotypic correlation, an analysis of the medical records of each patient was carried out. Results: Most common pathogenic variant (48%) in the sample is p.His1069Gln (c.3207C>A), located in exon 14 of the ATP7B gene. Pathogenic variants of p.Glu1064Lys (c.3190G>A)-20%-and p.Met769HisfsTer26 (c.2304insC)-8%-of exons 14 and 8 were also common. For patients with pathogenic alleles p.His1069Gln (c.3207C>A) and p.Glu1064Lys (c.3190G>A), typical deviations are mental and neurological manifestations of WD. In patients with the pathogenic allele p.Met769HisfsTer26 (c.2304insC), deviations are more characteristic of the liver and a combination of various symptoms that are atypical for WD. Conclusions: In this study, we were able to obtain differences in symptoms in patients with different pathogenic alleles of the ATP7B gene.
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Affiliation(s)
- Mikhail Garbuz
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Elena Ovchinnikova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Anna Ovchinnikova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Valeriya Vinokurova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Yulya Aristarkhova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Olga Kuziakova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Mariya Mashurova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Vadim Kumeiko
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
- A.V. Zhirmunsky National Scientific Center of Marine Biology Far Eastern Branch of Russian Academy of Sciences, Vladivostok 690041, Russia
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Choi W, Cha S, Kim K. Navigating the CRISPR/Cas Landscape for Enhanced Diagnosis and Treatment of Wilson's Disease. Cells 2024; 13:1214. [PMID: 39056796 PMCID: PMC11274827 DOI: 10.3390/cells13141214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) system continues to evolve, thereby enabling more precise detection and repair of mutagenesis. The development of CRISPR/Cas-based diagnosis holds promise for high-throughput, cost-effective, and portable nucleic acid screening and genetic disease diagnosis. In addition, advancements in transportation strategies such as adeno-associated virus (AAV), lentiviral vectors, nanoparticles, and virus-like vectors (VLPs) offer synergistic insights for gene therapeutics in vivo. Wilson's disease (WD), a copper metabolism disorder, is primarily caused by mutations in the ATPase copper transporting beta (ATP7B) gene. The condition is associated with the accumulation of copper in the body, leading to irreversible damage to various organs, including the liver, nervous system, kidneys, and eyes. However, the heterogeneous nature and individualized presentation of physical and neurological symptoms in WD patients pose significant challenges to accurate diagnosis. Furthermore, patients must consume copper-chelating medication throughout their lifetime. Herein, we provide a detailed description of WD and review the application of novel CRISPR-based strategies for its diagnosis and treatment, along with the challenges that need to be overcome.
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Affiliation(s)
- Woong Choi
- Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea;
| | - Seongkwang Cha
- Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea;
- Neuroscience Research Institute, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Kyoungmi Kim
- Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea;
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea
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Lafhal K, Sabir ES, Hakmaoui A, Hammoud M, Aimrane A, Najeh S, Assiri I, Berrachid A, Imad N, Boujemaa CA, Aziz F, El Hanafi FZ, Lalaoui A, Aamri H, Boyko I, Sánchez-Monteagudo A, Espinós C, Sab IA, Aboussair N, Bourrahouat A, Fdil N. Clinical, biochemical and molecular characterization of Wilson's disease in Moroccan patients. Mol Genet Metab Rep 2023; 36:100984. [PMID: 37323222 PMCID: PMC10267639 DOI: 10.1016/j.ymgmr.2023.100984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/23/2023] [Accepted: 05/30/2023] [Indexed: 06/17/2023] Open
Abstract
Background Wilson Disease (WD) is an autosomal recessive inherited metabolic disease caused by mutations in the ATP7B gene. WD is characterized by heterogeneous clinical presentations expressed by hepatic and neuropsychiatric phenotypes. The disease is difficult to diagnose, and misdiagnosed cases are commonly seen. Methods In this study, the presented symptoms of WD, the biochemical parameters as well as its natural history are described based on cases collected in Mohammed VI Hospital University of Marrakech (Morocco). We screened and sequenced 21 exons of ATP7B gene from 12 WD patients that confirmed through biochemical diagnosis. Results Mutational assessment of the ATP7B gene showed six homozygous mutations in 12 individuals however, 2 patients had no evidence of any mutation in promoter and exonic regions. All mutations are pathogenic and most were missense mutations. c.2507G > A (p.G836E), c.3694A > C (p.T1232P) and c.3310 T > C (p.C1104R) that were identified in 4 patients. The other mutations were a non-sense mutation (c.865C > T (p.C1104R)) detected in 2 patients, a splice mutation (c.51 + 4A > T) detected in 2 patients and a frameshift mutation (c.1746 dup (p.E583Rfs*25) detected in 2 patients. Conclusion Our study is the first molecular analysis in Moroccan patients with Wilson's disease, the ATP7B mutational spectrum in the Moroccan population is diverse and still unexplored.
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Affiliation(s)
- Karima Lafhal
- Metabolic Platform, Biochemistry Laboratory, Faculty of Medicine, Cadi Ayad University, Marrakech, Morocco
| | - Es-said Sabir
- Metabolic Platform, Biochemistry Laboratory, Faculty of Medicine, Cadi Ayad University, Marrakech, Morocco
| | - Abdelmalek Hakmaoui
- Center of Clinical Research, University Hospital Mohammed VI, Marrakech, Morocco
| | - Miloud Hammoud
- Metabolic Platform, Biochemistry Laboratory, Faculty of Medicine, Cadi Ayad University, Marrakech, Morocco
| | - Abdelmohcine Aimrane
- Metabolic Platform, Biochemistry Laboratory, Faculty of Medicine, Cadi Ayad University, Marrakech, Morocco
| | - Samira Najeh
- Metabolic Platform, Biochemistry Laboratory, Faculty of Medicine, Cadi Ayad University, Marrakech, Morocco
| | - Imane Assiri
- Metabolic Platform, Biochemistry Laboratory, Faculty of Medicine, Cadi Ayad University, Marrakech, Morocco
| | - Abdelaati Berrachid
- Metabolic Platform, Biochemistry Laboratory, Faculty of Medicine, Cadi Ayad University, Marrakech, Morocco
| | - Najwa Imad
- Mother-Child Hospital, Pediatric Department, Mohammed VI University Hospital, Cadi Ayad University, Marrakesh, Morocco
| | - Chaima Ait Boujemaa
- Center of Clinical Research, University Hospital Mohammed VI, Marrakech, Morocco
| | - Faissal Aziz
- National Center for Study and Research on Water and Energy, PO Box 511, Cadi Ayyad University, Marrakech., Morocco
| | - Fatima Zahra El Hanafi
- Mother-Child Hospital, Pediatric Department, Mohammed VI University Hospital, Cadi Ayad University, Marrakesh, Morocco
| | - Abdessamad Lalaoui
- Mother-Child Hospital, Pediatric Department, Mohammed VI University Hospital, Cadi Ayad University, Marrakesh, Morocco
| | - Hasna Aamri
- Mother-Child Hospital, Pediatric Department, Mohammed VI University Hospital, Cadi Ayad University, Marrakesh, Morocco
| | - Iryna Boyko
- Laboratory of Rare Neurodegenerative Diseases, Príncipe Felipe Research Center (CIPF), Valencia, Spain
| | - Ana Sánchez-Monteagudo
- Laboratory of Rare Neurodegenerative Diseases, Príncipe Felipe Research Center (CIPF), Valencia, Spain
- Joint Unit INCLIVA & IIS La Fe Rare Diseases, Valencia, Spain
| | - Carmen Espinós
- Laboratory of Rare Neurodegenerative Diseases, Príncipe Felipe Research Center (CIPF), Valencia, Spain
- Joint Unit INCLIVA & IIS La Fe Rare Diseases, Valencia, Spain
- Biotechnology Department, Faculty of Veterinary and Experimental Sciences, Catholic University of Valencia, Valencia, Spain
| | - Imane Ait Sab
- Mother-Child Hospital, Pediatric Department, Mohammed VI University Hospital, Cadi Ayad University, Marrakesh, Morocco
| | - Nisrine Aboussair
- Department of Medical Genetics, Mohammed VI University Hospital, Cadi Ayad University, Marrakesh, Morocco
| | - Aicha Bourrahouat
- Mother-Child Hospital, Pediatric Department, Mohammed VI University Hospital, Cadi Ayad University, Marrakesh, Morocco
| | - Naima Fdil
- Metabolic Platform, Biochemistry Laboratory, Faculty of Medicine, Cadi Ayad University, Marrakech, Morocco
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Xu H, Lv H, Chen X, Lian Y, Xing G, Wang Y, Hu R. Novel mutations in ATP7B in Chinese patients with Wilson's disease and identification of kidney disorder of thinning of the glomerular basement membrane. Front Neurol 2023; 14:1231605. [PMID: 37681011 PMCID: PMC10481399 DOI: 10.3389/fneur.2023.1231605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 08/02/2023] [Indexed: 09/09/2023] Open
Abstract
Introduction Wilson's disease is an autosomal recessive disorder caused by ATP7B pathogenic mutations. The hallmark of this disorder mainly consists of liver involvement, neurologic dysfunction and psychiatric features. In addition, the kidneys can also be affected by excessive copper deposition. Methods A total of 34 patients clinically diagnosed with WD were recruited. They underwent ATP7B gene sequencing and clinical data of symptoms, examination, and treatment were collected. Moreover, renal pathology information was also investigated. Results We identified 25 potentially pathogenic ATP7B variants (16 missense, 5 frameshift, 3 splicing variants and 1 large deletion mutation) in these 34 WD patients, 5 of which were novel. In our cases, the most frequent variant was c.2333G>T (R778L, 39.06%, exon 8), followed by c.2621C>T (A874V, 10.94%, exon 11) and c.3316G>A (V1106I, 7.81%, exon 11). Furthermore, we described the thinning of the glomerular basement membrane as a rare pathologically damaging feature of Wilson's disease for the first time. Additionally, two patients who received liver transplant were observed with good prognosis in present study. Discussion Our work expanded the spectrum of ATP7B variants and presented rare renal pathological feature in WD patients, which may facilitate the development of early diagnosis, counseling, treatment regimens of WD.
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Affiliation(s)
- Hongliang Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Hanyu Lv
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xin Chen
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yajun Lian
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Guolan Xing
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yingzi Wang
- Department of Renal Electron Microscopy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ruimin Hu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Yang D, Xiao P, Qiu B, Yu HF, Teng CB. Copper chaperone antioxidant 1: multiple roles and a potential therapeutic target. J Mol Med (Berl) 2023; 101:527-542. [PMID: 37017692 DOI: 10.1007/s00109-023-02311-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/23/2023] [Accepted: 03/26/2023] [Indexed: 04/06/2023]
Abstract
Copper (Cu) was recently demonstrated to play a critical role in cellular physiological and biochemical processes, including energy production and maintenance, antioxidation and enzymatic activity, and signal transduction. Antioxidant 1 (ATOX1), a chaperone of Cu previously named human ATX1 homologue (HAH1), has been found to play an indispensable role in maintaining cellular Cu homeostasis, antioxidative stress, and transcriptional regulation. In the past decade, it has also been found to be involved in a variety of diseases, including numerous neurodegenerative diseases, cancers, and metabolic diseases. Recently, increasing evidence has revealed that ATOX1 is involved in the regulation of cell migration, proliferation, autophagy, DNA damage repair (DDR), and death, as well as in organism development and reproduction. This review summarizes recent advances in the research on the diverse physiological and cytological functions of ATOX1 and the underlying mechanisms of its action in human health and diseases. The potential of ATOX1 as a therapeutic target is also discussed. This review aims to pose unanswered questions related to ATOX1 biology and explore the potential use of ATOX1 as a therapeutic target.
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Affiliation(s)
- Dian Yang
- Animal Development Biology Laboratory, College of Life Science, Northeast Forestry University, Harbin, 150040, People's Republic of China
| | - Pengyu Xiao
- Animal Development Biology Laboratory, College of Life Science, Northeast Forestry University, Harbin, 150040, People's Republic of China
| | - Botao Qiu
- Animal Development Biology Laboratory, College of Life Science, Northeast Forestry University, Harbin, 150040, People's Republic of China
| | - Hai-Fan Yu
- Animal Development Biology Laboratory, College of Life Science, Northeast Forestry University, Harbin, 150040, People's Republic of China.
| | - Chun-Bo Teng
- Animal Development Biology Laboratory, College of Life Science, Northeast Forestry University, Harbin, 150040, People's Republic of China.
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Gromadzka G, Bendykowska M, Przybyłkowski A. Wilson’s Disease—Genetic Puzzles with Diagnostic Implications. Diagnostics (Basel) 2023; 13:diagnostics13071287. [PMID: 37046505 PMCID: PMC10093728 DOI: 10.3390/diagnostics13071287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/12/2023] [Accepted: 03/18/2023] [Indexed: 03/30/2023] Open
Abstract
(1) Introduction: Wilson’s disease (WND) is an autosomal recessive disorder of copper metabolism. The WND gene is ATP7B, located on chromosome 13. WND is characterized by high clinical variability, which causes diagnostic difficulties. (2) Methods: The PubMed, Science Direct, and Wiley Online Library medical databases were reviewed using the following phrases: “Wilson’s disease”, “ATP7B genotype”, “genotype-phenotype”, “epigenetics”, “genetic modifiers”, and their combinations. Publications presenting the results of experimental and clinical studies, as well as review papers, were selected, which concerned: (i) the diversity of genetic strategies and tests used in WND diagnosis; (ii) the difficulties of genetic diagnosis, including uncertainty as to the pathogenicity of variants; (iii) genetic counseling; (iv) phenotypic effects of ATP7B variants in patients with WND and in heterozygous carriers (HzcWND); (v) genetic and epigenetics factors modifying the clinical picture of the disease. (3) Results and conclusions: The genetic diagnosis of WND is carried out using a variety of strategies and tests. Due to the large number of known variants in the ATP7B gene (>900), the usefulness of genetic tests in routine diagnostics is still relatively small and even analyses performed using the most advanced technologies, including next-generation sequencing, require additional tests, including biochemical evidence of abnormal copper metabolism, to confirm the diagnosis of WND. Pseudodominant inheritance, the presence of three various pathogenic variants in the same patient, genotypes indicating the possibility of segmental uniparental disomy, have been reported. Genotype–phenotype relationships in WND are complex. The ATP7B genotype, to some extent, determines the clinical picture of the disease, but other genetic and epigenetic modifiers are also relevant.
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Roy S, Ghosh S, Ray J, Ray K, Sengupta M. Missing heritability of Wilson disease: a search for the uncharacterized mutations. Mamm Genome 2023; 34:1-11. [PMID: 36462057 DOI: 10.1007/s00335-022-09971-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 11/24/2022] [Indexed: 12/05/2022]
Abstract
Wilson disease (WD), a copper metabolism disorder caused by mutations in ATP7B, manifests heterogeneous clinical features. Interestingly, in a fraction of clinically diagnosed WD patients, mutations in ATP7B appears to be missing. In this review we discuss the plausible explanations of this missing heritability and propose a workflow that can identify the hidden mutations. Mutation analyses of WD generally includes targeted sequencing of ATP7B exons, exon-intron boundaries, and rarely, the proximal promoter region. We propose that variants in the distal cis-regulatory elements and/or deep intronic variants that impact splicing might well represent the hidden mutations. Heterozygous del/ins that remain refractory to conventional PCR-sequencing method may also represent such mutations. In this review, we also hypothesize that mutations in the key copper metabolism genes, like, ATOX1, COMMD1, and SLC31A1, could possibly lead to a WD-like phenotype. In fact, WD does present overlapping symptoms with other rare genetic disorders; hence, the possibility of a misdiagnosis and thus adding to missing heritability cannot be excluded. In this regard, it seems that whole-genome analysis will provide a comprehensive and rapid molecular diagnosis of WD. However, considering the associated cost for such a strategy, we propose an alternative customized screening schema of WD which include targeted sequencing of ATP7B locus as well as other key copper metabolism genes. Success of such a schema has been tested in a pilot study.
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Affiliation(s)
- Shubhrajit Roy
- S. N. Pradhan Centre for Neurosciences, University of Calcutta, Kolkata, India
- Post-doctoral Fellow, Physiology Department, Johns Hopkins University, Baltimore, USA
| | - Sampurna Ghosh
- Department of Genetics, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, 700019, India
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada
| | - Jharna Ray
- S. N. Pradhan Centre for Neurosciences, University of Calcutta, Kolkata, India
| | - Kunal Ray
- Ramakrishna Mission Vivekananda Educational and Research Institute, Narendrapur, Kolkata, 700 103, India.
| | - Mainak Sengupta
- Department of Genetics, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, 700019, India.
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Penning LC, Berenguer M, Czlonkowska A, Double KL, Dusek P, Espinós C, Lutsenko S, Medici V, Papenthin W, Stremmel W, Willemse J, Weiskirchen R. A Century of Progress on Wilson Disease and the Enduring Challenges of Genetics, Diagnosis, and Treatment. Biomedicines 2023; 11:biomedicines11020420. [PMID: 36830958 PMCID: PMC9953205 DOI: 10.3390/biomedicines11020420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 02/04/2023] Open
Abstract
Wilson disease (WD) is a rare, inherited metabolic disorder manifested with varying clinical presentations including hepatic, neurological, psychiatric, and ophthalmological features, often in combination. Causative mutations in the ATP7B gene result in copper accumulation in hepatocytes and/or neurons, but clinical diagnosis remains challenging. Diagnosis is complicated by mild, non-specific presentations, mutations exerting no clear effect on protein function, and inconclusive laboratory tests, particularly regarding serum ceruloplasmin levels. As early diagnosis and effective treatment are crucial to prevent progressive damage, we report here on the establishment of a global collaboration of researchers, clinicians, and patient advocacy groups to identify and address the outstanding challenges posed by WD.
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Affiliation(s)
- Louis C. Penning
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands
- Correspondence: (L.C.P.); (R.W.)
| | - Marina Berenguer
- Digestive Medicine Department, Ciberehd & IISLaFe, Hospital U. i P. La Fe, University of Valencia, 46010 Valenci, Spain
| | - Anna Czlonkowska
- Second Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland
| | - Kay L. Double
- Brain and Mind Centre and School of Medical Sciences (Neuroscience), The University of Sydney, Sydney, NSW 2006, Australia
| | - Petr Dusek
- Department of Radiology, Charles University and General University Hospital, 128 08 Prague, Czech Republic
- Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, 128 08 Prague, Czech Republic
| | - Carmen Espinós
- Rare Neurodegenerative Diseases Lab, Centro de Investigacion Principe Felipe, 46012 Valencia, Spain
| | - Svetlana Lutsenko
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 1800, USA
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 1800, USA
| | - Valentina Medici
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA 59817, USA
| | - Wiebke Papenthin
- German Society for Wilson disease Patients (Morbus Wilson e.V.), Zehlendorfer Damm 119, D-14532 Kleinnachnow, Germany
| | - Wolfgang Stremmel
- Private Practice for Internal Medicine, Beethovenstraße 2, D-76530 Baden-Baden, Germany
| | - Jose Willemse
- Dutch Society for Liver Disease Patients (Nederlandse Leverpatienten Vereniging), 3828 NS Hoogland, The Netherlands
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital Aachen, D-52074 Aachen, Germany
- Correspondence: (L.C.P.); (R.W.)
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Garbuz MM, Ovchinnikova AA, Kumeiko VV. Design, Optimization and Validation of the ARMS PCR Protocol for the Rapid Diagnosis of Wilson's Disease Using a Panel of 14 Common Mutations for the European Population. Genes (Basel) 2022; 13:1940. [PMID: 36360177 PMCID: PMC9690040 DOI: 10.3390/genes13111940] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/17/2022] [Accepted: 10/20/2022] [Indexed: 08/15/2023] Open
Abstract
BACKGROUND Wilson's disease (WD) is an autosomal recessive inherited disorder of copper metabolism resulting from various mutations in the ATP7B gene. Despite good knowledge and successful treatment options, WD is a severe disease that leads to disability, destructively affecting the quality of life of patients. Currently, none of the available laboratory tests can be considered universal and specific for the diagnosis of WD. Therefore, the introduction of genetic diagnostic methods that allow for the identification of the root cause at any stage over the course of the disease gave hope for an earlier solution of diagnostic issues in patients with WD. METHODS A method for the genetic diagnosis of WD based on ARMS PCR, DreamTaq Green PCR Master Mix and modified primers has been developed. This method is able to detect 14 mutant alleles: p.His1069Gln, p.Glu1064Lys, p.Met769HisfsTer26, p.Gly710Ser, p.Ser744Pro, p.Ala1135GlnfsTer13, p.Arg778Leu, p.Arg1041Trp, p.Arg616Gln, p.Arg778Gly, p.Trp779*, p.Val834Asp, p.Gly943Ser and p.3222_3243+21del43. RESULTS The primers for all mutations were highly specific with an absence of wild-type amplification. All the results were validated by direct DNA Sanger sequencing. CONCLUSIONS This fast and economical method provides coverage for the identified common mutations, thereby making ARMS PCR analysis using DreamTaq Green PCR Master Mix and modified primers feasible and attractive for large-scale routine use.
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Affiliation(s)
| | | | - Vadim Vladimirovich Kumeiko
- Institute of Life Sciences and Biomedicine, Far Eastern Federal University, Vladivostok 690922, Russia
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch of Russian Academy of Sciences, Federal University, Vladivostok 690041, Russia
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Panzer M, Viveiros A, Schaefer B, Baumgartner N, Seppi K, Djamshidian A, Todorov T, Griffiths WJH, Schott E, Schuelke M, Eurich D, Stättermayer AF, Bomford A, Foskett P, Vodopiutz J, Stauber R, Pertler E, Morell B, Tilg H, Müller T, Kiechl S, Jimenez‐Heredia R, Weiss KH, Hahn SH, Janecke A, Ferenci P, Zoller H. Synonymous mutation in adenosine triphosphatase copper-transporting beta causes enhanced exon skipping in Wilson disease. Hepatol Commun 2022; 6:1611-1619. [PMID: 35271763 PMCID: PMC9234614 DOI: 10.1002/hep4.1922] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 11/25/2021] [Accepted: 12/22/2021] [Indexed: 12/21/2022] Open
Abstract
Wilson disease (WD) is caused by biallelic pathogenic variants in adenosine triphosphatase copper-transporting beta (ATP7B); however, genetic testing identifies only one or no pathogenic ATP7B variant in a number of patients with WD. Synonymous single-nucleotide sequence variants have been recognized as pathogenic in individual families. The aim of the present study was to evaluate the prevalence and disease mechanism of the synonymous variant c.2292C>T (p.Phe764=) in WD. A cohort of 280 patients with WD heterozygous for a single ATP7B variant was investigated for the presence of c.2292C>T (p.Phe764=). In this cohort of otherwise genetically unexplained WD, the allele frequency of c.2292C>T (p.Phe764=) was 2.5% (14 of 560) compared to 7.1 × 10-6 in the general population (2 of 280,964 in the Genome Aggregation Database; p < 10-5 ; Fisher exact test). In an independent United Kingdom (UK) cohort, 2 patients with WD homozygous for p.Phe764= were identified. RNA analysis of ATP7B transcripts from patients homozygous or heterozygous for c.2292C>T and control fibroblasts showed that this variant caused high expression of an ATP7B transcript variant lacking exon 8. Conclusion: The synonymous ATP7B variant c.2292C>T (p.Phe764=) causes abnormal messenger RNA processing of ATP7B transcripts and is associated with WD in compound heterozygotes and homozygotes.
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Affiliation(s)
- Marlene Panzer
- Department of Medicine IMedical University of InnsbruckInnsbruckAustria
- VASCage Research Center on Vascular Ageing and StrokeInnsbruckAustria
| | - André Viveiros
- Department of Medicine IMedical University of InnsbruckInnsbruckAustria
| | - Benedikt Schaefer
- Department of Medicine IMedical University of InnsbruckInnsbruckAustria
| | - Nadja Baumgartner
- Department of Medicine IMedical University of InnsbruckInnsbruckAustria
| | - Klaus Seppi
- Department of NeurologyMedical University of InnsbruckInnsbruckAustria
| | - Atbin Djamshidian
- Department of NeurologyMedical University of InnsbruckInnsbruckAustria
| | - Theodor Todorov
- Department of Medical Genetics and Molecular BiologyUniversity Hospital LozenetzSofiaBulgaria
| | - William J. H. Griffiths
- Cambridge Liver UnitCambridge University Hospitals National Health Service (NHS) Foundation TrustCambridgeUK
| | - Eckart Schott
- Helios Klinikum Emil von Behring GmbHKlinik für Innere Medizin IIBerlinGermany
| | - Markus Schuelke
- Department of NeuropediatricsCharité University Medical Center BerlinBerlinGermany
| | - Dennis Eurich
- Department of SurgeryCharité University Medical Center BerlinBerlinGermany
| | - Albert Friedrich Stättermayer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University ViennaViennaAustria
| | - Adrian Bomford
- Institute of Liver StudiesKing's College Hospital NHS Foundation TrustLondonUK
| | - Pierre Foskett
- Institute of Liver StudiesKing's College Hospital NHS Foundation TrustLondonUK
| | - Julia Vodopiutz
- Division of Pediatric Pulmology, Allergology, and EndocrinologyDepartment of Pediatrics and Adolescent MedicineComprehensive Center for PediatricsMedical University of ViennaViennaAustria
| | - Rudolf Stauber
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineMedical University of GrazGrazAustria
| | - Elke Pertler
- Department of Medicine IMedical University of InnsbruckInnsbruckAustria
- Christian Doppler Laboratory on Iron and Phosphate BiologyInnsbruckAustria
| | - Bernhard Morell
- Department of Gastroenterology and HepatologyUniversity Hospital ZurichZurichSwitzerland
| | - Herbert Tilg
- Department of Medicine IMedical University of InnsbruckInnsbruckAustria
| | - Thomas Müller
- Department of Pediatrics IMedical University of InnsbruckInnsbruckAustria
| | - Stefan Kiechl
- Department of NeurologyMedical University of InnsbruckInnsbruckAustria
| | - Raul Jimenez‐Heredia
- Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesViennaAustria
- Department of Pediatrics and Adolescent MedicineMedical University of ViennaViennaAustria
- St. Anna Children's Cancer Research InstituteViennaAustria
| | - Karl Heinz Weiss
- Internal MedicineKrankenhaus Salem der Evangelischen StadtmissionHeidelbergGermany
| | - Si Houn Hahn
- University of Washington School of MedicineSeattle Children’s HospitalSeattleWashingtonUSA
| | - Andreas Janecke
- Department of Pediatrics IMedical University of InnsbruckInnsbruckAustria
| | - Peter Ferenci
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University ViennaViennaAustria
| | - Heinz Zoller
- Department of Medicine IMedical University of InnsbruckInnsbruckAustria
- Christian Doppler Laboratory on Iron and Phosphate BiologyInnsbruckAustria
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11
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Zhou D, Jia S, Yi L, Wu Z, Song Y, Zhang B, Li Y, Yang X, Xu A, Li X, Zhang W, Duan W, Li Z, Qi S, Chen Z, Ouyang Q, Jia J, Huang J, Ou X, You H. Identification of potential modifier genes in Chinese patients with Wilson disease. Metallomics 2022; 14:mfac024. [PMID: 35357466 PMCID: PMC9154322 DOI: 10.1093/mtomcs/mfac024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 03/29/2022] [Indexed: 11/29/2022]
Abstract
The mutations in modifier genes may contribute to some inherited diseases including Wilson disease (WD). This study was designed to identify potential modifier genes that contribute to WD. A total of 10 WD patients with single or no heterozygous ATP7B mutations were recruited for whole-exome sequencing (WES). Five hundred and thirteen candidate genes, of which the genetic variants present in at least two patients, were identified. In order to clarify which proteins might be involved in copper transfer or metabolism processes, the isobaric tags for relative and absolute quantitation (iTRAQ) was performed to identify the differentially expressed proteins between normal and CuSO4-treated cell lines. Thirteen genes/proteins were identified by both WES and iTRAQ, indicating that disease-causing variants of these genes may actually contribute to the aberrant copper ion accumulation. Additionally, the c.86C > T (p.S29L) mutation in the SLC31A2 gene (coding CTR2) has a relative higher frequency in our cohort of WD patients (6/191) than reported (0.0024 in gnomAD database) in our healthy donors (0/109), and CTR2S29L leads to increased intracellular Cu concentration and Cu-induced apoptosis in cultured cell lines. In conclusion, the WES and iTRAQ approaches successfully identified several disease-causing variants in potential modifier genes that may be involved in the WD phenotype.
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Affiliation(s)
- Donghu Zhou
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Siyu Jia
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Liping Yi
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Zhen Wu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Yi Song
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Bei Zhang
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Yanmeng Li
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Xiaoxi Yang
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Anjian Xu
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Xiaojin Li
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Wei Zhang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Weijia Duan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Zhenkun Li
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Saiping Qi
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Zhibin Chen
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Qin Ouyang
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Jian Huang
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
| | - Hong You
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, On behalf of China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group, Beijing, China
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12
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Sánchez-Monteagudo A, Ripollés E, Berenguer M, Espinós C. Wilson's Disease: Facing the Challenge of Diagnosing a Rare Disease. Biomedicines 2021; 9:1100. [PMID: 34572285 PMCID: PMC8471362 DOI: 10.3390/biomedicines9091100] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/20/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychiatric, ophthalmological, and other disturbances. WD has a specific treatment, so that early diagnosis is crucial to avoid disease progression and its devastating consequences. The clinical diagnosis is based on the Leipzig score, which considers clinical, histological, biochemical, and genetic data. However, even patients with an initial WD diagnosis based on a high Leipzig score may harbor other conditions that mimic the WD's phenotype (Wilson-like). Many patients are diagnosed using current available methods, but others remain in an uncertain area because of bordering ceruloplasmin levels, inconclusive genetic findings and unclear phenotypes. Currently, the available biomarkers for WD are ceruloplasmin and copper in the liver or in 24 h urine, but they are not solid enough. Therefore, the characterization of biomarkers that allow us to anticipate the evolution of the disease and the monitoring of new drugs is essential to improve its diagnosis and prognosis.
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Affiliation(s)
- Ana Sánchez-Monteagudo
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; (A.S.-M.); (E.R.)
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
| | - Edna Ripollés
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; (A.S.-M.); (E.R.)
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
| | - Marina Berenguer
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
- Hepatology-Liver Transplantation Unit, Digestive Medicine Service, IIS La Fe and CIBER-EHD, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
- Department of Medicine, Universitat de València, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Carmen Espinós
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; (A.S.-M.); (E.R.)
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
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13
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Maung MT, Carlson A, Olea-Flores M, Elkhadragy L, Schachtschneider KM, Navarro-Tito N, Padilla-Benavides T. The molecular and cellular basis of copper dysregulation and its relationship with human pathologies. FASEB J 2021; 35:e21810. [PMID: 34390520 DOI: 10.1096/fj.202100273rr] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 06/23/2021] [Accepted: 07/07/2021] [Indexed: 12/16/2022]
Abstract
Copper (Cu) is an essential micronutrient required for the activity of redox-active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu+ -transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in carcinogenesis as a promotor of tumor growth and an inducer of redox stress in cancer cells. Cu also plays role in cancer treatment as a component of drugs and a regulator of drug sensitivity and uptake. In this review, we provide an overview of the current knowledge of Cu metabolism and transport and its relation to various human pathologies.
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Affiliation(s)
- May T Maung
- Department of Molecular Biology and Biochemistry, Wesleyan University, Middletown, CT, USA
| | - Alyssa Carlson
- Department of Molecular Biology and Biochemistry, Wesleyan University, Middletown, CT, USA
| | - Monserrat Olea-Flores
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Guerrero, Mexico
| | - Lobna Elkhadragy
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
| | - Kyle M Schachtschneider
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA.,Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA.,National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Napoleon Navarro-Tito
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Guerrero, Mexico
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14
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Couchonnal E, Bouchard S, Sandahl TD, Pagan C, Lion-François L, Guillaud O, Habes D, Debray D, Lamireau T, Broué P, Fabre A, Vanlemmens C, Sobesky R, Gottrand F, Bridoux-Henno L, Belmalih A, Poujois A, Brunet AS, Lachaux A, Bost M. ATP7B variant spectrum in a French pediatric Wilson disease cohort. Eur J Med Genet 2021; 64:104305. [PMID: 34400371 DOI: 10.1016/j.ejmg.2021.104305] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 06/12/2021] [Accepted: 08/12/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND/AIM The spectrum of ATP7B variants varies significantly according to geographic distribution, and there is insufficient data on the variants observed in the French population. METHODS Clinical data of 113 children included in the French WD national registry were gathered from March 01, 1995 to July 01, 2020. Data included epidemiological, clinical, laboratory, genetics. RESULTS Diagnosis was made at a mean age of 11.0 ± 4.1 years (range 1-18 years). At diagnosis, 91 patients (79.8 %) had hepatic manifestations, 18 (15.8 %) presented neurological manifestations, and 4 patients (3.5 %) were asymptomatic. Only 29 patients (25 %) were homozygous for a variant. We have found a total of 102 different variants including 14 novel variants. Recurrent variant p.His1069Gln was the most prevalent, n = 31 alleles (14,2%), with only seven homozygous; in contrast 55% of variants are identified in only one family. 45% were truncating variants. In respect of mutated exon, the three most prevalent were exon 14 (16.5%), exon 8 (13.8%), and exon 3 (11.5%). When considering patients with two Nonsense / Frameshift variants as a group and those with two Missense variants, we found significantly lower ceruloplasmin for the former: 2.8 ± 0.7 mg/dl vs 8.4 ± 5mg/dl (p<0.05). CONCLUSION p.His1069Gln is the most frequent variant (14,2%) and exons 14, 8, and 2 of the ATP7B gene account for 41.7% of total variants. However, there is significant heterogeneity in the French population concerning the other ATP7B variants. Nonsense / Frameshift variants were associated with lower ceruloplasmin levels.
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Affiliation(s)
- Eduardo Couchonnal
- Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany.
| | | | - Thomas Damgaard Sandahl
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Cecile Pagan
- Department of Biochemistry and Molecular Biology, LBMMS, Hospices Civils de Lyon, France
| | - Laurence Lion-François
- Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Olivier Guillaud
- Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Dalila Habes
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Pediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, Le Kremlin-Bicêtre, France
| | - Dominique Debray
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Inserm U1193, Hepatinov, University of Paris Saclay, Orsay, France
| | - Thierry Lamireau
- Children's Hospital, Paediatric Gastroenterology Unit, Bordeaux, France
| | - Pierre Broué
- Children University Hospital, Metabolic Disease Department, Toulouse, France
| | - Alexandre Fabre
- APH, Timone Enfant, Service de Pédiatrie Multidisciplinaire, Marseille, France; Aix Marseille Univ, INSERM, MMG, Marseille, France
| | - Claire Vanlemmens
- University Hospital of Besancon, Paediatric Gastroenterology Unit, Besacon, France
| | - Rodolphe Sobesky
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Paul Brousse Hospital, Hepatobiliary Centre, Hepatobiliary Centre, France
| | - Frederic Gottrand
- Univ- Lille, CHU Lille, UMR1286 Department of Pediatric Gastroenterology Hepatology and Nutrition, Lille, France
| | | | - Abdelouahed Belmalih
- Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Aurelia Poujois
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; French National Rare Disease Reference Centre "Wilson's Disease and Other Copper-related Rare Diseases", Rothschild Foundation Hospital, Neurology Department, Paris, France
| | - Anne Sophie Brunet
- Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France
| | - Alain Lachaux
- Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Claude Bernard Lyon 1 University Lyon, France
| | - Muriel Bost
- Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Department of Biochemistry and Molecular Biology, LBMMS, Hospices Civils de Lyon, France
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15
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Xiao Z, Yang Y, Huang H, Tang H, Liu L, Tang J, Shi X. Molecular analysis of 53 Chinese families with Wilson's disease: Six novel mutations identified. Mol Genet Genomic Med 2021; 9:e1735. [PMID: 34324271 PMCID: PMC8457707 DOI: 10.1002/mgg3.1735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/18/2021] [Accepted: 05/25/2021] [Indexed: 11/06/2022] Open
Abstract
Background Wilson's disease (WD) is a rare autosomal recessive inherited disorder that is induced by defects of the ATP7B gene and characterized by damage to the liver and nervous system caused by aberrant copper metabolism. The identification of pathogenic mutations on two homologous chromosomes has become the gold standard for the diagnosis of WD. Methods Sanger sequencing and multiplex ligation‐dependent probe amplification (MLPA) were combined to establish a genetic diagnosis for patients from 53 unrelated Chinese WD families. Results Biallelic mutations were detected by Sanger sequencing in 50 of the probands, while single heterozygous mutations were detected in the remaining three probands. A total of 45 diverse pathogenic mutations were detected, and 6 previously unreported mutations were involved. Five asymptomatic patients were screened from 85 family members of 38 probands participating in the study. Conclusion This study contributes to the enlargement of the mutational spectrum of the ATP7B gene among the population of China and highlights the significance of genetic testing for asymptomatic patients.
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Affiliation(s)
- Zhongyan Xiao
- Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.,Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Yuan Yang
- Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.,Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), ICU, Peking University Cancer Hospital & Institute, Beijing, 100142, People's Republic of China
| | - Hui Huang
- Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Haiyan Tang
- Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Liqun Liu
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Jianguang Tang
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Xiaoliu Shi
- Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
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16
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Weiskirchen R, Penning LC. COMMD1, a multi-potent intracellular protein involved in copper homeostasis, protein trafficking, inflammation, and cancer. J Trace Elem Med Biol 2021; 65:126712. [PMID: 33482423 DOI: 10.1016/j.jtemb.2021.126712] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 12/10/2020] [Accepted: 01/04/2021] [Indexed: 12/11/2022]
Abstract
Copper is a trace element indispensable for life, but at the same time it is implicated in reactive oxygen species formation. Several inherited copper storage diseases are described of which Wilson disease (copper overload, mutations in ATP7B gene) and Menkes disease (copper deficiency, mutations in ATP7A gene) are the most prominent ones. After the discovery in 2002 of a novel gene product (i.e. COMMD1) involved in hepatic copper handling in Bedlington terriers, studies on the mechanism of action of COMMD1 revealed numerous non-copper related functions. Effects on hepatic copper handling are likely mediated via interactions with ATP7B. In addition, COMMD1 has many more interacting partners which guide their routing to either the plasma membrane or, often in an ubiquitination-dependent fashion, trigger their proteolysis via the S26 proteasome. By stimulating NF-κB ubiquitination, COMMD1 dampens an inflammatory reaction. Finally, targeting COMMD1 function can be a novel approach in the treatment of tumors.
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Affiliation(s)
- Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital Aachen, Aachen, Germany
| | - Louis C Penning
- Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Department of Clinical Sciences of Companion Animals, 3584 CM, Utrecht, the Netherlands.
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17
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Corbee RJ, Penning LC. COMMD1 Exemplifies the Power of Inbred Dogs to Dissect Genetic Causes of Rare Copper-Related Disorders. Animals (Basel) 2021; 11:ani11030601. [PMID: 33668783 PMCID: PMC7996361 DOI: 10.3390/ani11030601] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/22/2021] [Accepted: 02/22/2021] [Indexed: 12/13/2022] Open
Abstract
Wilson's Disease is a rare autosomal recessive disorder in humans, often presenting with hepatic copper overload. Finding the genetic cause of a rare disease, especially if it is related to food constituents like the trace element copper, is a Herculean task. This review describes examples of how the unique population structure of in-bred dog strains led to the discovery of a novel gene and two modifier genes involved in inherited copper toxicosis. COMMD1, after the discovery in 2002, was shown to be a highly promiscuous protein involved in copper transport, protein trafficking/degradation, regulation of virus replication, and inflammation. Mutations in the ATP7A and ATP7B proteins in Labrador retrievers and Dobermann dogs resulted in a wide variation in hepatic copper levels in these breeds. To our knowledge, numerous dog breeds with inherited copper toxicosis of unknown genetic origin exist. Therefore, the possibility that men's best friend will provide new leads in rare copper storage diseases seems realistic.
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Wilson disease: 30-year data on epidemiology, clinical presentation, treatment modalities and disease outcomes from two tertiary Greek centers. Eur J Gastroenterol Hepatol 2020; 32:1545-1552. [PMID: 32118851 DOI: 10.1097/meg.0000000000001670] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Wilson disease is a rare genetic disorder of copper metabolism with a wide range of clinical presentations. The aim of this study is to describe the 30-year clinical experience in the management of Wilson disease patients followed at two Greek referral centers. METHODS A retrospective chart review was performed to identify past and present Wilson disease patients diagnosed during the last 30 years. RESULTS Sixty-three patients were included. The median age of diagnosis was 19 (3-59) years, while nine (14%) patients were older than 40 years old. Clinical presentation included asymptomatic liver disease (57.1%), neurological disease (20.6%), overt liver disease (12.7%), acute liver failure (6.3%) and other (3.2%). Kayser-Fleischer rings were detected in 27/62 with a higher frequency in neurologic patients (P < 0.001). Ceruloplasmin values were low in 55/63 with significantly lower values in patients with neurological disease (P = 0.048) and in cirrhotic patients (P = 0.017). Increased 24-hour urine copper was measured in 59/63 patients. D-penicillamine was administered in 56/63 patients (88.8%), followed by trientine (6/63, 9.5%), while one patient needed liver transplantation at baseline. At least one treatment switch was performed in 18 patients. By the end of follow-up, all non-cirrhotic patients (25/25) were stable, 3/23 (13%) cirrhotic developed decompensated liver disease, two developed HCC, three received a liver transplant and two died. Five out of 13 neurologic patients had persisting symptoms despite treatment. CONCLUSION Wilson disease presents with a wide spectrum of clinical manifestations and should be investigated even in older patients, as early diagnosis, close follow-up and treatment monitoring usually provide favorable outcomes.
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Woimant F, Poujois A, Bloch A, Jordi T, Laplanche J, Morel H, Collet C. A novel deep intronic variant in ATP7B in five unrelated families affected by Wilson disease. Mol Genet Genomic Med 2020; 8:e1428. [PMID: 32770663 PMCID: PMC7549599 DOI: 10.1002/mgg3.1428] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 06/02/2020] [Accepted: 07/02/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Wilson disease is an autosomal recessive metabolic disorder resulting from accumulation of excess copper especially in the liver and brain. This disease is mainly characterized by hepatic disorders and less frequently by neuro-psychiatric disturbances. This recessive disease is due to mutation in ATP7B, which codes for an ATPase involved in copper-transport across the plasma membrane. Molecular diagnosis of WD is positive in approximately 98% of cases. Also, in few cases, WD patients present a single deleterious mutation (heterozygous) or no mutation after sanger and NGS standard sequencing analysis of ATP7B. Therefore, in these problematic WD cases, we hypothesized that deleterious mutations reside in intronic regions of ATP7B. METHODS Complete ATP7B gene was sequenced by Next Generation Sequencing including its promoter. RESULTS Five unrelated families with Wilson disease shared the same novel, deep intronic NG_008806.1 (ATP7B_v001):c.2866-1521G>A variant in ATP7B. Analysis of RNA transcripts from primary fibroblasts of one patient confirmed the deleterious impact of the intronic variant on splicing and its likely pathologic effect in this compound heterozygote. CONCLUSION This discovery of a novel intronic mutation in ATP7B has improved the molecular diagnosis of WD in the French patient cohort to greater than 98%. Thus, we recommend complete sequencing of ATP7B gene, including introns, as a molecular diagnostic approach in cases of clinically confirmed WD which lack pathogenic exon or promoter variants in one or both alleles.
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Affiliation(s)
- France Woimant
- National reference Centre for Wilson’s Disease (CRMR Wilson)Department of NeurologyRothschild HospitalParisFrance
- Department of NeurologyLariboisiere University HospitalAPHPParisFrance
| | - Aurelia Poujois
- National reference Centre for Wilson’s Disease (CRMR Wilson)Department of NeurologyRothschild HospitalParisFrance
- Department of NeurologyLariboisiere University HospitalAPHPParisFrance
| | - Adrien Bloch
- Department of Biochemistry and Molecular BiologyLariboisiere University HospitalAPHPParisFrance
| | - Tabaras Jordi
- National reference Centre for Wilson’s Disease (CRMR Wilson)Department of NeurologyRothschild HospitalParisFrance
| | - Jean‐Louis Laplanche
- Department of Biochemistry and Molecular BiologyLariboisiere University HospitalAPHPParisFrance
| | - Hélène Morel
- Department of Biochemistry and Molecular BiologyLariboisiere University HospitalAPHPParisFrance
| | - Corinne Collet
- Department of Biochemistry and Molecular BiologyLariboisiere University HospitalAPHPParisFrance
- INSERM U1132University Paris‐Diderot and Department of RheumatologyLariboisiere University HospitalParisFrance
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Balashova MS, Tuluzanovskaya IG, Glotov OS, Glotov AS, Barbitoff YA, Fedyakov MA, Alaverdian DA, Ivashchenko TE, Romanova OV, Sarana AM, Scherbak SG, Baranov VS, Filimonov MI, Skalny AV, Zhuchenko NA, Ignatova TM, Asanov AY. The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation. J Trace Elem Med Biol 2020; 59:126420. [PMID: 31708252 DOI: 10.1016/j.jtemb.2019.126420] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Revised: 10/21/2019] [Accepted: 10/22/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Wilson's disease (WD) is a rare inherited disorder caused by mutations in the ATP7B gene resulting in copper accumulation in different organs. However, data on ATP7B mutation spectrum in Russia and worldwide are insufficient and contradictory. The objective of the present study was estimation of the frequency of ATP7B gene mutations in the Russian population of WD patients. MATERIALS AND METHODS 75 WDpatients were examined by next-generation sequencing (NGS). A targeted panel NimbleGen SeqCap EZ Choice: 151012_HG38_CysFib_EZ_HX3 (ROCHE)was designed for analysis of ATP7B gene and possible modifier genes. Retrospective assessment of a diagnostic WD score (Leipzig, 2001) was also performed. RESULTS 31 mutations in ATP7B gene were detected. Two most frequent mutations were c.3207C > A (51,85% of alleles) and c.3190 G > A (8,64% of alleles). Single rare mutations were detected in 29% of cases. In 96% cases mutations of both copies of the ATP7B were revealed. We also observed 3 novel potentially pathogenic variants which were not previously described (c.1870-8A > G, c.3655A > T (p.Ile1219Phe), c.3036dupC (p.Lys1013fs). For 25% of patients at the time of the manifestation the diagnosis WD could not be established using the earlier proposed diagnostic score. There was a remarkable delay in diagnosis for the majority of patients. Only 33% of patients WD was diagnosed in three months after the first symptoms, 29%patients - in 3-12 months, 30% - in 1-10 years, in 8% - more than 10 years. Generally, clinical appearance of WD may be rather variable at manifestation and genetic profiling at this step is the only way to confirm the presence of WD.
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Affiliation(s)
- Mariya S Balashova
- Sechenov First Moscow State Medical University, Moscow, Russia; Center of Genetics and Reproductive Medicine «Genetico», Moscow, Russia.
| | | | - Oleg S Glotov
- D.O.Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, Russia; St.Petersburg State Health Care Establishment the City Hospital №40, St. Petersburg, Russia; Saint Petersburg State University, St. Petersburg, Russia
| | - Andrey S Glotov
- D.O.Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, Russia; St.Petersburg State Health Care Establishment the City Hospital №40, St. Petersburg, Russia; Saint Petersburg State University, St. Petersburg, Russia
| | - Yury A Barbitoff
- Saint Petersburg State University, St. Petersburg, Russia; Bioinformatics Institute, St. Petersburg, Russia
| | - Mikhail A Fedyakov
- St.Petersburg State Health Care Establishment the City Hospital №40, St. Petersburg, Russia; Saint Petersburg State University, St. Petersburg, Russia
| | - Diana A Alaverdian
- St.Petersburg State Health Care Establishment the City Hospital №40, St. Petersburg, Russia
| | - Tatiana E Ivashchenko
- D.O.Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, Russia
| | - Olga V Romanova
- D.O.Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, Russia; St.Petersburg State Health Care Establishment the City Hospital №40, St. Petersburg, Russia
| | - Andrey M Sarana
- St.Petersburg State Health Care Establishment the City Hospital №40, St. Petersburg, Russia; Saint Petersburg State University, St. Petersburg, Russia
| | - Sergey G Scherbak
- St.Petersburg State Health Care Establishment the City Hospital №40, St. Petersburg, Russia; Saint Petersburg State University, St. Petersburg, Russia
| | - Vladislav S Baranov
- D.O.Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, Russia; Saint Petersburg State University, St. Petersburg, Russia
| | | | - Anatoly V Skalny
- Sechenov First Moscow State Medical University, Moscow, Russia; Taipei Medical University, Taipei, Taiwan
| | | | - Tatiana M Ignatova
- Center of Endosurgery and Lithotripsy (CELT), Moscow, Russia; Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow, Russia
| | - Aliy Y Asanov
- Sechenov First Moscow State Medical University, Moscow, Russia
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Wallace DF, Dooley JS. ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease. Hum Genet 2020; 139:1065-1075. [PMID: 32248359 DOI: 10.1007/s00439-020-02161-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 03/30/2020] [Indexed: 12/20/2022]
Abstract
Wilson disease (WD) is a genetic disorder of copper metabolism caused by variants in the copper transporting P-type ATPase gene ATP7B. Estimates for WD population prevalence vary with 1 in 30,000 generally quoted. However, some genetic studies have reported much higher prevalence rates. The aim of this study was to estimate the population prevalence of WD and the pathogenicity/penetrance of WD variants by determining the frequency of ATP7B variants in a genomic sequence database. A catalogue of WD-associated ATP7B variants was constructed, and then, frequency information for these was extracted from the gnomAD data set. Pathogenicity of variants was assessed by (a) comparing gnomAD allele frequencies against the number of reports for variants in the WD literature and (b) using variant effect prediction algorithms. 231 WD-associated ATP7B variants were identified in the gnomAD data set, giving an initial estimated population prevalence of around 1 in 2400. After exclusion of WD-associated ATP7B variants with predicted low penetrance, the revised estimate showed a prevalence of around 1 in 20,000, with higher rates in the Asian and Ashkenazi Jewish populations. Reanalysis of other recent genetic studies using our penetrance criteria also predicted lower population prevalences for WD in the UK and France than had been reported. Our results suggest that differences in variant penetrance can explain the discrepancy between reported epidemiological and genetic prevalences of WD. They also highlight the challenge in defining penetrance when assigning causality to some ATP7B variants.
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Affiliation(s)
- Daniel F Wallace
- Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
| | - James S Dooley
- Division of Medicine, UCL Institute for Liver and Digestive Health, University College London Medical School (Royal Free Campus), London, UK
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Ma TJ, Sun GL, Yao F, Yang ZL. Wilson disease associated with immune thrombocytopenia: A case report and review of the literature. World J Clin Cases 2019; 7:2630-2636. [PMID: 31559303 PMCID: PMC6745329 DOI: 10.12998/wjcc.v7.i17.2630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 06/30/2019] [Accepted: 07/20/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Wilson disease (WD) is a genetic disorder of hepatic copper excretion, leading to copper accumulation in various tissues. The manifestations are quite variable, and hemolytic anemia is the most common hematological presentation. WD associated with thrombocytopenia is very rare.
CASE SUMMARY We report the case of an 11-year-old Chinese girl with WD that was associated with immune thrombocytopenia (ITP). Thrombocytopenia was the initial chief complaint for her to visit a hematologist, and ITP was diagnosed based on the results of a bone marrow biopsy and positive antiplatelet autoantibodies. About two weeks before the thrombocytopenia was found, the patient developed drooling. Tremors developed in her right hand about one week after being diagnosed with ITP, after which she was admitted to our hospital. Further evaluations were performed. Ceruloplasmin was decreased, with an increased level of copper in her 24-h urine excretion. Kayser Fleischer's ring (K-F ring) was positive. The ultrasound showed liver cirrhosis, and brain magnetic resonance imaging showed that the lenticular nucleus, caudate nucleus, and brainstem presented a low signal intensity in T1-weighted images and high signal intensity in T2-weighted images. WD was diagnosed and a genetic analysis was performed. A compound heterozygous mutation in ATP7B was detected; c.2333G>T (p.Arg778Leu) in exon 8 and c.3809A>G (p.Asn1270Ser) in exon 18. The former was inherited from her father and the latter from her mother. However, her parents showed normal liver function and negative K-F rings. Such a compound mutation in a case of WD associated with ITP in children has not been published previously.
CONCLUSION WD can associate with thrombocytopenia but the mechanism is still unclear. We recommend that antiplatelet autoantibodies should be tested in WD patients with thrombocytopenia in future to verify the association.
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Affiliation(s)
- Tian-Jiao Ma
- Department of Pediatrics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Gui-Lian Sun
- Department of Pediatrics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Fang Yao
- Department of Pediatrics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Zhi-Liang Yang
- Department of Pediatrics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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In-silico analysis of novel p.(Gly14Ser) variant of ATOX1 gene: plausible role in modulating ATOX1-ATP7B interaction. Mol Biol Rep 2019; 46:3307-3313. [PMID: 30980273 DOI: 10.1007/s11033-019-04791-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 03/28/2019] [Indexed: 10/27/2022]
Abstract
Clinical heterogeneity is commonly observed in Wilson disease (WD), including cases with identical ATP7B mutations. It is thought to be an outcome of impairment in other genes involved in cellular copper homeostasis in addition to the mutations in the ATP7B gene. ATOX1, a copper chaperone that delivers copper to ATP7B, is a potential genetic modifier of WD. In the present study, we analyzed the genetic variations in the ATOX1 gene in 50 WD patients and 60 controls. We identified four novel variants, of which, the coding region variant c.40G > A, p.(Gly14Ser) was observed in 2% alleles. Interestingly, p.(Gly14Ser) was seen with an early onset age, reduced serum ceruloplasmin level and manifestations of liver and brain in a WD patient unlike the other having identical ATP7B mutation but normal ATOX1 alleles. Further, computational analysis predicted that p.(Gly14Ser) substitution, in the critical copper binding motif (MXCXG14C) of the protein, affects the protein-protein interaction involved in copper sharing and transfer between ATOX1 and ATP7B-MBD4. Our findings suggest that p.(Gly14Ser) variant of ATOX1 might play a role as a genetic modifier leading to phenotypic variation in WD.
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Medici V, LaSalle JM. Genetics and epigenetic factors of Wilson disease. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:S58. [PMID: 31179295 PMCID: PMC6531661 DOI: 10.21037/atm.2019.01.67] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 01/25/2019] [Indexed: 12/13/2022]
Abstract
Wilson disease (WD) is a complex condition due to copper accumulation mainly in the liver and brain. The genetic base of WD is represented by pathogenic mutations of the copper-transporting gene ATP7B with consequent lack of copper excretion through the biliary tract. ATP7B is the only gene so far identified and known to be responsible for the development of the disease. Our understanding of the disease has been evolving as functional studies have associated specific disease-causing mutations with specific copper-transporter impairments. The most frequent variant in patients of European descent is the H1069Q missense mutation and it has been associated with protein misfolding, aberrant phosphorylation of the P-domain, and altered ATP binding orientation and affinity. Conversely, there is much less understanding of the relation between the genotype and the clinical manifestations of WD. WD is characterized by a highly varied and unpredictable presentation with different combined hepatic, neurological, and psychiatric symptoms. Several studies have attempted to correlate genotype and phenotype but the most recent evidences on larger populations failed to identify a relation between genotype and clinical presentations. Given that so far also modifier genes have not shown convincing association with WD, there is growing interest to identify epigenetic mechanisms of gene expression regulation as underlying the onset and progression of WD phenotype. Evidence from animal models indicated changes in methionine metabolism regulation with possible effects on DNA methylation. Mouse models of WD have indicated transcript level changes of genes related to DNA methylation in fetal and adult livers. And finally, evidence is accumulating regarding DNA methylation changes in patients with WD. It is unexplored how ATP7B genetic mutations combine with epigenetic changes to affect the phenotype. In conclusion, WD is a genetic disease with a complex regulation of its phenotype that includes molecular genetics and epigenetic mechanisms.
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Affiliation(s)
- Valentina Medici
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, California, USA
| | - Janine M. LaSalle
- Department of Medical Microbiology and Immunology, University of California Davis, Sacramento, California, USA
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Chen YC, Yu H, Wang RM, Xie JJ, Ni W, Zhang Y, Dong Y, Wu ZY. Contribution of intragenic deletions to mutation spectrum in Chinese patients with Wilson's disease and possible mechanism underlying ATP7B gross deletions. Parkinsonism Relat Disord 2019; 62:128-133. [PMID: 30655162 DOI: 10.1016/j.parkreldis.2019.01.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 12/20/2018] [Accepted: 01/01/2019] [Indexed: 11/17/2022]
Abstract
INTRODUCTION Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism due to ATP7B pathogenic mutations. Disease manifestations can be prevented if early diagnosis and effective treatment are given. Direct sequencing is routinely used to confirm WD diagnosis, but cannot identify gross rearrangements. METHODS Sanger sequencing of ATP7B was performed in 142 newly recruited WD index patients. The clinical effects of identified variants were classified according to American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Multiplex ligation-dependent probe amplification (MLPA) was performed in 168 WD cases with clinical WD unexplained by Sanger sequencing, selected from our total case series of 774 WD patients. After identifying gross rearrangements within ATP7B, the breakpoints were determined by long-range PCR and direct sequencing. RESULTS In the 142 WD patients, we identified 71 sequence alterations in ATP7B, of which 15 were novel; 14 of these were classified as 'pathogenic' or 'likely pathogenic', including 2 intronic variants affecting splice sites. In 6 of 168 WD patients, MLPA identified four heterozygous gross ATP7B deletions. One was a whole gene deletion, and three were intragenic deletions which were mapped to breakpoint locations, revealing non-homologous end joining. CONCLUSION Intragenic deletions are responsible for WD and non-homologous end joining could be the pathogenesis, therefore the detection of intragenic deletions should be included in comprehensive genetic testing for WD.
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Affiliation(s)
- Yu-Chao Chen
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China; Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Hao Yu
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Rou-Min Wang
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Juan-Juan Xie
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Wang Ni
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Yue Zhang
- Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yi Dong
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China.
| | - Zhi-Ying Wu
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China.
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Poujois A, Woimant F. Wilson's disease: A 2017 update. Clin Res Hepatol Gastroenterol 2018; 42:512-520. [PMID: 29625923 DOI: 10.1016/j.clinre.2018.03.007] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 02/27/2018] [Accepted: 03/08/2018] [Indexed: 02/04/2023]
Abstract
Wilson's disease (WD) is characterised by a deleterious accumulation of copper in the liver and brain. It is one of those rare genetic disorders that benefits from effective and lifelong treatments that have dramatically transformed the prognosis of the disease. In Europe, its clinical prevalence is estimated at between 1.2 and 2/100,000 but the genetic prevalence is higher, at around 1/7000. Incomplete penetrance of the gene or the presence of modifier genes may account for the difference between the calculated genetic prevalence and the number of patients diagnosed with WD. The clinical spectrum of WD is broader as expected with mild clinical presentations and late onset of the disease after the age of 40 in 6% of patients. WD is usually suspected when ceruloplasmin and serum copper levels are low and 24h urinary copper excretion is elevated. Recently, a major diagnostic advance was achieved with implementation of the direct assay of "free copper", or exchangeable copper (CuEXC). The relative exchangeable copper (REC) that corresponds to the ratio between CuEXC and total serum copper enables a diagnosis of WD with high sensitivity and specificity when REC>18.5%. Moreover, CuEXC values at diagnosis are a marker of extrahepatic involvement and its severity. A value of >2.08μmol/L is suggestive of corneal and brain involvement (Se=86%, Sp=94%), and the disease will be more clinically and radiologically severe as values rise. The use of FibroScan® is becoming more widespread to assess liver stiffness measurements in WD patients. 6.6kPa is considered to be a threshold value between mild and moderate fibrosis, whereas a value higher than 8.4 is indicative of severe fibrosis. More studies are now necessary to confirm the usefulness of Fibroscan® in managing chronic therapy for WD patients. Treatment of this disease is based on an initial active and prolonged chelating phase (with D-Penicillamine or Trientine) followed by maintenance with Trientine or zinc salt. The two major problems that may be encountered are neurological worsening during the initial phase and non-compliance with treatment during maintenance therapy. Liver transplantation is the recommended therapeutic option in WD with acute liver failure or end-stage liver cirrhosis; its indication should be considered when neurological status deteriorates rapidly despite effective chelation. Regular clinical, biological and liver ultrasound follow-up is essential to evaluate efficacy, tolerance and treatment compliance, but also to detect the onset of hepatocellular carcinoma on a cirrhotic liver. There are hopes in the near future with the introduction of a new chelator and inhibitor of copper absorption, tetrathiomolybdate (TTM) and the development of gene therapy.
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Affiliation(s)
- Aurélia Poujois
- Neurology Department, AP-HP, Lariboisière University Hospital, Paris, France; National Reference Centre for Wilson's Disease, AP-HP, Lariboisière University Hospital, Paris, France.
| | - France Woimant
- Neurology Department, AP-HP, Lariboisière University Hospital, Paris, France; National Reference Centre for Wilson's Disease, AP-HP, Lariboisière University Hospital, Paris, France
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Członkowska A, Litwin T, Dusek P, Ferenci P, Lutsenko S, Medici V, Rybakowski JK, Weiss KH, Schilsky ML. Wilson disease. Nat Rev Dis Primers 2018; 4:21. [PMID: 30190489 PMCID: PMC6416051 DOI: 10.1038/s41572-018-0018-3] [Citation(s) in RCA: 530] [Impact Index Per Article: 75.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Wilson disease (WD) is a potentially treatable, inherited disorder of copper metabolism that is characterized by the pathological accumulation of copper. WD is caused by mutations in ATP7B, which encodes a transmembrane copper-transporting ATPase, leading to impaired copper homeostasis and copper overload in the liver, brain and other organs. The clinical course of WD can vary in the type and severity of symptoms, but progressive liver disease is a common feature. Patients can also present with neurological disorders and psychiatric symptoms. WD is diagnosed using diagnostic algorithms that incorporate clinical symptoms and signs, measures of copper metabolism and DNA analysis of ATP7B. Available treatments include chelation therapy and zinc salts, which reverse copper overload by different mechanisms. Additionally, liver transplantation is indicated in selected cases. New agents, such as tetrathiomolybdate salts, are currently being investigated in clinical trials, and genetic therapies are being tested in animal models. With early diagnosis and treatment, the prognosis is good; however, an important issue is diagnosing patients before the onset of serious symptoms. Advances in screening for WD may therefore bring earlier diagnosis and improvements for patients with WD.
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Affiliation(s)
- Anna Członkowska
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland.
| | - Tomasz Litwin
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Petr Dusek
- Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Peter Ferenci
- Internal Medicine 3, Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Svetlana Lutsenko
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Valentina Medici
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California, Davis, Sacramento, CA, USA
| | - Janusz K Rybakowski
- Department of Adult Psychiatry, Poznań University of Medical Sciences, Poznań, Poland
| | - Karl Heinz Weiss
- Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Michael L Schilsky
- Section of Digestive Diseases and Transplantation and Immunology, Department of Medicine and Surgery, Yale University School of Medicine, New Haven, CT, USA
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High genetic carrier frequency of Wilson's disease in France: discrepancies with clinical prevalence. BMC MEDICAL GENETICS 2018; 19:143. [PMID: 30097039 PMCID: PMC6086069 DOI: 10.1186/s12881-018-0660-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 07/31/2018] [Indexed: 12/11/2022]
Abstract
Background Wilson’s disease (WD) is a rare autosomal recessive metabolic disease caused by ATP7B gene mutations tat cause excessively high copper levels, particularly in the liver and brain. The WD phenotype varies in terms of its clinical presentation and intensity. Diagnosing this metabolic disorder is important as a lifelong treatment, based on the use of copper chelating agents or zinc salts, is more effective if it’s started early. Worldwide prevalence of WD is variable, with an average of 1/30,000. In France, a recent study based on French health insurance data estimated the clinical prevalence of the disease to be around 3/200,000. Methods To estimate the genetic prevalence of WD in France, we analysed the ATP7B gene by Next Generation Sequencing from a large French cohort of indiscriminate subjects. Results We observed a high heterozygous carrier frequency of ATP7B in France. Among the 697 subjects studied, 18 variants classified as pathogenic or probably pathogenic were found at heterozygous level in 22 subjects (22 alleles/1394 alleles), yielding a prevalence of 0.032 or 1/31 subjects. Conclusions This considerable and unexplained discrepancy between the heterozygous carrier frequency and the clinical prevalence of WD may be explained by the clinical variability, the incomplete penetrance and the existence of modifiers genes. It suggests that the molecular analysis of ATP7B should be interpreted with caution, always alongside copper assays (ceruloplasmin, relative exchangeable copper, 24 h-urinary copper excretion) with particular respect to exome sequencing.
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Wang C, Zhou W, Huang Y, Yin H, Jin Y, Jia Z, Zhang A, Liu Z, Zheng B. Presumed missense and synonymous mutations in ATP7B gene cause exon skipping in Wilson disease. Liver Int 2018; 38:1504-1513. [PMID: 29637721 DOI: 10.1111/liv.13754] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 03/28/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Wilson disease is an inborn error of metabolism caused by abnormalities of the copper-transporting protein-encoding gene ATP7B. Recently, the phenomenon of exon skipping, in which exonic mutations result in abnormal splicing, has been associated with various diseases. The present study investigated the splicing defects of the ATP7B exonic variants identified in a cohort of 44 patients with Wilson disease. METHOD All patients were analysed for ATP7B gene by direct sequencing or multiplex ligation-dependent probe amplification analysis. To identify the potential pathogenicity of the candidate mutations that may induce exon skipping, both in vivo RT-PCR analysis using RNA from peripheral leukocytes and in vitro functional splicing by minigene construction were conducted. RESULTS The patterns of inheritance of the mutations in ATP7B identified in 44 patients exhibited homozygotes (7 patients), compound heterozygotes (32 patients) and heterozygotes (5 patients). In all patients, we detected 25 different ATP7B mutations, including 17 missenses, 1 frameshift, 3 nonsenses, 2 exonic deletions and 2 splicing alteration. In these mutations, 4 mutations have not been previously described in the literature or entered in human genome mutation database. Furthermore, we identified synonymous mutation c.4014T>A and missense mutation R919G caused exon skipping in the ATP7B mRNA transcript. CONCLUSION Our results suggest that aberrant exon skipping associated to putative splicing enhancer disruption and silencer creation is one previously unrecognized mechanism in Wilson disease. What is more, the multiplex ligation-dependent probe amplification assay for the detection of exon deletions may be valuable in individuals with clinical Wilson disease diagnosis where one or no mutation has been identified by sequencing.
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Affiliation(s)
- Chunli Wang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Zhou
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Yan Huang
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Hanjun Yin
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Yu Jin
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Zhanjun Jia
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Aihua Zhang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Zhifeng Liu
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Bixia Zheng
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
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Shim JO, Yang HR, Moon JS, Chang JY, Ko JS, Park SS, Seo JK. Multiplex Ligation-dependent Probe Amplification Analysis Subsequent to Direct DNA Full Sequencing for Identifying ATP7B Mutations and Phenotype Correlations in Children with Wilson Disease. J Korean Med Sci 2018; 33:e177. [PMID: 29930488 PMCID: PMC6010744 DOI: 10.3346/jkms.2018.33.e177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 04/17/2018] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Mutations in ATP7B cause Wilson disease (WD). However, direct DNA full sequencing cannot detect all mutations in patients with WD. Multiplex ligation-dependent probe amplification (MLPA) analysis is reportedly useful in increasing the diagnostic yield in other genetic disorders with large deletions or insertions. The aim of this study was to evaluate whether the detection rate of ATP7B mutations can be increased by using MLPA. METHODS We enrolled 114 children with WD from 104 unrelated families based on biochemical tests and direct DNA full sequencing. The patients with one or zero mutant allele were investigated using MLPA. We analyzed phenotypic correlations. RESULTS Total allele frequency by full sequencing was 87.5%. Full sequencing revealed two mutant alleles in 80 of 104 unrelated children. One mutant allele was detected in 22 children, and no mutations were found in two children. Novel mutations including small deletions with frameshift mutations were identified by DNA sequencing. MLPA revealed no gross deletion or duplication in 24 children with one or zero mutant alleles. The number of detected mutations was not associated with hepatic manifestation, age of onset, Kayser-Fleischer ring, ceruloplasmin, and urinary Cu concentrations. CONCLUSION MLPA showed a limited role to increase the mutation detection rate in children who do not receive a definite genetic diagnosis of WD through DNA full sequencing. This finding suggests that large deletions or duplications might be extremely rare in WD. Further development is needed to improve the genetic diagnosis of WD.
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Affiliation(s)
- Jung Ok Shim
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Hye Ran Yang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jin Soo Moon
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Ju Young Chang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Sung Sup Park
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Kee Seo
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
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Guillaud O, Brunet AS, Mallet I, Dumortier J, Pelosse M, Heissat S, Rivet C, Lachaux A, Bost M. Relative exchangeable copper: A valuable tool for the diagnosis of Wilson disease. Liver Int 2018; 38:350-357. [PMID: 28719006 DOI: 10.1111/liv.13520] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 07/13/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Measuring of the relative exchangeable copper seems to be a promising tool for the diagnosis of Wilson disease. The aim of our study is to determine the performance of REC for the diagnosis of Wilson disease in a population of patients with chronic liver diseases. METHODS Measuring of exchangeable serum copper levels and relative exchangeable copper was performed in a group of Wilson disease patients at diagnosis or at clinical deterioration because of non-compliance (group 1, n=9), a group of stable WD patients (group 2, n=40), and two groups of patients (adult and paediatric) followed for non-Wilsonian liver diseases (group 3, n=103 and group 4, n=49 respectively). RESULTS Exchangeable serum copper (N: 0.6-1.1 μmol/L) was significantly higher in group 1 (mean 2.2±0.7 μmol/L) compared to the other three groups: group 2=0.9±0.4 μmol/L, group 3=1.2±0.4 μmol/L, group 4=1.1±0.3 μmol/L (P<0.05). Relative exchangeable copper was significantly higher in Wilson disease patients group 1 and 2 (mean 52.6% and 43.8%) compared to patients suffering from other liver diseases (mean 7.1% and 5.9%) (P<0.05). CONCLUSIONS Our study confirms that the determination of relative exchangeable copper is a highly valuable tool for the diagnosis of Wilson disease.
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Affiliation(s)
- Olivier Guillaud
- French National Reference Center for Wilson Disease, Femme Mère Enfant Hospital, Hospices civils de Lyon, Bron, France.,Department of Hepatogastroenterology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Anne-Sophie Brunet
- French National Reference Center for Wilson Disease, Femme Mère Enfant Hospital, Hospices civils de Lyon, Bron, France.,Department of Pediatric Hepatogastroenterology and Nutrition, Femme mère enfant Hospital, Hospices Civils de Lyon, Bron, France
| | - Isabelle Mallet
- French National Reference Center for Wilson Disease, Femme Mère Enfant Hospital, Hospices civils de Lyon, Bron, France.,Department of Biochemistry and Molecular biology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Jérôme Dumortier
- French National Reference Center for Wilson Disease, Femme Mère Enfant Hospital, Hospices civils de Lyon, Bron, France.,Department of Hepatogastroenterology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.,University Claude Bernard Lyon 1, Lyon, France
| | - Martine Pelosse
- French National Reference Center for Wilson Disease, Femme Mère Enfant Hospital, Hospices civils de Lyon, Bron, France.,Department of Pediatric Hepatogastroenterology and Nutrition, Femme mère enfant Hospital, Hospices Civils de Lyon, Bron, France
| | - Sophie Heissat
- French National Reference Center for Wilson Disease, Femme Mère Enfant Hospital, Hospices civils de Lyon, Bron, France.,Department of Pediatric Hepatogastroenterology and Nutrition, Femme mère enfant Hospital, Hospices Civils de Lyon, Bron, France
| | - Christine Rivet
- French National Reference Center for Wilson Disease, Femme Mère Enfant Hospital, Hospices civils de Lyon, Bron, France.,Department of Pediatric Hepatogastroenterology and Nutrition, Femme mère enfant Hospital, Hospices Civils de Lyon, Bron, France
| | - Alain Lachaux
- French National Reference Center for Wilson Disease, Femme Mère Enfant Hospital, Hospices civils de Lyon, Bron, France.,Department of Pediatric Hepatogastroenterology and Nutrition, Femme mère enfant Hospital, Hospices Civils de Lyon, Bron, France.,University Claude Bernard Lyon 1, Lyon, France
| | - Muriel Bost
- French National Reference Center for Wilson Disease, Femme Mère Enfant Hospital, Hospices civils de Lyon, Bron, France.,Department of Biochemistry and Molecular biology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.,Department of Molecular Genetics and Genetic Diseases of Metabolism, Department of Biology and Pathology, Hospices Civils de Lyon, Bron, France
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Kieffer DA, Medici V. Wilson disease: At the crossroads between genetics and epigenetics-A review of the evidence. LIVER RESEARCH 2017; 1:121-130. [PMID: 29270329 PMCID: PMC5734098 DOI: 10.1016/j.livres.2017.08.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Environmental factors, including diet, exercise, stress, and toxins, profoundly impact disease phenotypes. This review examines how Wilson disease (WD), an autosomal recessive genetic disorder, is influenced by genetic and environmental inputs. WD is caused by mutations in the copper-transporter gene ATP7B, leading to the accumulation of copper in the liver and brain, resulting in hepatic, neurological, and psychiatric symptoms. These symptoms range in severity and can first appear anytime between early childhood and old age. Over 300 disease-causing mutations in ATP7B have been identified, but attempts to link genotype to the phenotypic presentation have yielded little insight, prompting investigators to identify alternative mechanisms, such as epigenetics, to explain the highly varied clinical presentation. Further, WD is accompanied by structural and functional abnormalities in mitochondria, potentially altering the production of metabolites that are required for epigenetic regulation of gene expression. Notably, environmental exposure affects the regulation of gene expression and mitochondrial function. We present the "multi-hit" hypothesis of WD progression, which posits that the initial hit is an environmental factor that affects fetal gene expression and epigenetic mechanisms and subsequent "hits" are environmental exposures that occur in the offspring after birth. These environmental hits and subsequent changes in epigenetic regulation may impact copper accumulation and ultimately WD phenotype. Lifestyle changes, including diet, increased physical activity, stress reduction, and toxin avoidance, might influence the presentation and course of WD, and therefore may serve as potential adjunctive or replacement therapies.
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Demily C, Parant F, Cheillan D, Broussolle E, Pavec A, Guillaud O, Restier L, Lachaux A, Bost M. Screening of Wilson's disease in a psychiatric population: difficulties and pitfalls. A preliminary study. Ann Gen Psychiatry 2017; 16:19. [PMID: 28392828 PMCID: PMC5379609 DOI: 10.1186/s12991-017-0142-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 03/25/2017] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Wilson's disease (WD) is a rare autosomal-recessive, inherited disorder caused by a mutation in the copper-transporting gene ATP7B affecting the liver and nervous system. About 30% of patients with WD may initially present with psychiatric symptoms, and diagnosis can be difficult to establish. The objectives of the present preliminary study were [1] to evaluate the relevance of serum copper (Cu) and ceruloplasmin (Cp) measures in hospitalized patients with psychiatric disorders; and [2] to identify possible mutations in the ATP7B gene in patients with abnormal biological copper profile. METHODS All psychiatric patients who participated in this study were hospitalized in Saint-Jean de Dieu Hospital (Lyon, France). Cp was measured by immunoturbidimetry and serum Cu by inductively coupled plasma-optical emission spectrometry. When Cp and serum Cu levels were inferior to, respectively, 0.18 g/L and 0.88 mg/L in combination with atypical psychiatric presentations, complete clinical examinations were performed by multidisciplinary physicians specialized in WD. In addition, mutation detection in the ATP7B gene was performed. RESULTS A total of 269 patients completed the study. (1) 51 cases (19%) showed both decreased Cp and Cu concentrations. (2) Molecular genetic tests were performed in 29 patients, and one ATP7B mutation (heterozygous state) was found in four patients. We identified three different missense mutations: p.His1069Gln, c.3207C>A (exon 14), p.Pro1379Ser, c.4135C>T (exon 21) and p.Thr1434Met, c.4301C>T (exon 21). No pathogenic mutation on either ATP7B allele was detected. CONCLUSION Results of Cp and/or serum Cu concentrations below the normal limits are common in patients with psychiatric disorders and nonrelevant and/or informative for the WD diagnosis. WD diagnosis is based on a combination of clinical and biological arguments. Psychiatric patients with suspicion of WD should be evaluated in a reference center. Trial registration CPP Lyon Sud-Est IVNo 10/044, CNIL No DR-2011-470, Afssaps No B100832-40 and CCTIRS No 10.612 bis, registered 8 June 2010.
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Affiliation(s)
- Caroline Demily
- GénoPsy, Center for the Detection and Management of Psychiatric Disorders of Genetic Origin, Pôle Ouest, Hôpital le Vinatier & UMR 5229 (CNRS & Lyon University), 95 Bld Pinel, 69677 Bron cedex, France
- National Reference Center for Wilson’s disease, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - François Parant
- Pharmaco-Toxicology, Biochemistry and Molecular Biology Unit, Hôpital Édouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - David Cheillan
- Laboratory of Inherited Metabolic Diseases, Centre de Biologie Est, Hospices Civils de Lyon, Bron, France
| | - Emmanuel Broussolle
- National Reference Center for Wilson’s disease, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
- Neurology Unit C, Cognitive Neurosciences Center, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon; Claude Bernard-Lyon 1 University; CNRS UMR 5229, Bron, France
| | | | - Olivier Guillaud
- National Reference Center for Wilson’s disease, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
- Hepato-Gastroenterology Department, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Lioara Restier
- National Reference Center for Wilson’s disease, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
- Gastroenterology, Hepatology and Pediatric Nutrition Department, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Alain Lachaux
- National Reference Center for Wilson’s disease, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
- Gastroenterology, Hepatology and Pediatric Nutrition Department, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Muriel Bost
- Laboratory of Inherited Metabolic Diseases, Centre de Biologie Est, Hospices Civils de Lyon, Bron, France
- National Reference Center for Wilson’s disease, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
- Pharmaco-Toxicology, Biochemistry and Molecular Biology Unit, Hôpital Édouard Herriot, Hospices Civils de Lyon, Lyon, France
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Abstract
Wilson disease (WD) is an autosomal-recessive disorder of hepatocellular copper deposition caused by pathogenic variants in the copper-transporting gene, ATP7B. Early detection and treatment are critical to prevent lifelong neuropsychiatric, hepatic, and systemic disabilities. Due to the marked heterogeneity in age of onset and clinical presentation, the diagnosis of Wilson disease remains challenging to physicians today. Direct sequencing of the ATP7B gene is the most sensitive and widely used confirmatory testing method, and concurrent biochemical testing improves diagnostic accuracy. More than 600 pathogenic variants in ATP7B have been identified, with single-nucleotide missense and nonsense mutations being the most common, followed by insertions/deletions, and, rarely, splice site mutations. The prevalence of Wilson disease varies by geographic region, with higher frequency of certain mutations occurring in specific ethnic groups. Wilson disease has poor genotype-phenotype correlation, although a few possible modifiers have been proposed. Improving molecular genetic studies continue to advance our understanding of the pathogenesis, diagnosis, and screening for Wilson disease.
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Affiliation(s)
- Irene J Chang
- Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Si Houn Hahn
- Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA, USA.
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Intragenic Deletions in ATP7B as an Unusual Molecular Genetics Mechanism of Wilson's Disease Pathogenesis. PLoS One 2016; 11:e0168372. [PMID: 27992490 PMCID: PMC5167361 DOI: 10.1371/journal.pone.0168372] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 11/29/2016] [Indexed: 01/17/2023] Open
Abstract
Wilson’s disease (WD) is an autosomal recessive disorder caused by mutations in the ATP7B resulting in copper overload in the liver and brain. Direct sequencing is routinely used to confirm WD diagnosis; however, partial and whole gene deletions in the heterozygous state cannot be detected by exon amplification since the normal allele will mask its presence. The aim of the present work was to search for unusual mutational events in the unexplained WD cases and to provide insight into the mechanisms. Out of 1420 clinically and biochemically confirmed WD samples received between 2000 and 2014 for routine mutation analysis, we were unable to detect mutant alleles in 142 samples, after extensive sequencing analysis. We used selective amplification and MLPA to identify the partial gene deletions and identified three different partial gene deletions in seven different families. All three deletions were fully characterized at the DNA sequence level. We report the first hemizygous case with WD due to intragenic deletion in the ATP7B (c.3134_3556+689del). This novel deletion resulted from an excision event mediated by consensus sequences in an AluSq2 repeat element and could be traced to micro homologous end joining (MMEJ). Finally, we determined the prevalence of the three deletions in DNA samples from a multinational group of WD patients. Our results emphasize the need for searching mutant alleles beyond routine methods and highlight that large ATP7B deletions are rare, but account for a detectable proportion in some WD patients. Screening for gene aberrations will further improve mutation detection in patients with unidentified ATP7B mutations presenting with clinical manifestations of WD.
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Lv T, Li X, Zhang W, Zhao X, Ou X, Huang J. Recent advance in the molecular genetics of Wilson disease and hereditary hemochromatosis. Eur J Med Genet 2016; 59:532-539. [PMID: 27592149 DOI: 10.1016/j.ejmg.2016.08.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 07/12/2016] [Accepted: 08/31/2016] [Indexed: 02/07/2023]
Abstract
Metabolic liver diseases such as Wilson disease (WD) and hereditary hemochromatosis (HH) possess complicated pathogenesis and typical hereditary characteristics with the hallmarks of a deficiency in metal metabolism. Mutations in genes encoding ATPase, Cu + transporting, beta polypeptide (ATP7B) and hemochromatosis (HFE) or several non-HFE genes are considered to be causative for WD and HH, respectively. Although the identification of novel mutations in ATP7B for WD and HFE or the non-HFE genes for HH has increased, especially with the application of whole genome sequencing technology in recent years, the biological function of the identified mutations, as well as genotype-phenotype correlations remain to be explored. Further analysis of the causative gene mutation would be critical to clarify the mechanisms underlying specific disease phenotypes. In this review, we therefore summarize the recent advances in the molecular genetics of WD and HH including the updated mutation spectrums and the correlation between genotype and phenotype, with an emphasis on biological functional studies of the individual mutations identified in WD and HH. The weakness of the current functional studies and analysis for the clinical association of the individual mutation was also discussed. These works are essential for the understanding of the association between genotypes and phenotypes of these inherited metabolic liver diseases.
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Affiliation(s)
- Tingxia Lv
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xuan-wu District, Beijing, 100050, China.
| | - Xiaojin Li
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xuan-wu District, Beijing, 100050, China.
| | - Wei Zhang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xuan-wu District, Beijing, 100050, China.
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xuan-wu District, Beijing, 100050, China.
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xuan-wu District, Beijing, 100050, China.
| | - Jian Huang
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xuan-wu District, Beijing, 100050, China.
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Targeted next-generation sequencing of the ATP7B gene for molecular diagnosis of Wilson disease. Clin Biochem 2015; 49:166-71. [PMID: 26483271 DOI: 10.1016/j.clinbiochem.2015.10.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Revised: 09/09/2015] [Accepted: 10/14/2015] [Indexed: 02/08/2023]
Abstract
OBJECTIVES In recent years, next-generation sequencing (NGS) technologies, which enable high throughput sample processing at relatively lower costs, are adopted in both research and clinical settings. A multiplex PCR-based NGS assay to identify mutations in the ATP7B gene for routine molecular diagnosis of Wilson disease was evaluated in comparison with the gold standard direct Sanger sequencing. DESIGN AND METHODS Five multiplex PCRs to amplify the partial promoter, 5' untranslated and the entire coding regions of the ATP7B gene were designed. Indexed paired-end libraries were generated from the pooled amplicons using Nextera XT DNA Sample Preparation Kit and subjected to NGS on the MiSeq platform. DNA from the peripheral blood of 12 patients with Wilson disease, 2 B-lymphocyte cell lines and 3 external quality assurance samples were sequenced by the MiSeq and Sanger sequencing. RESULTS Complete coverage was achieved across the targeted bases without any drop-out sequences. The observed read depth in a single run with 20 samples was >100X. Comparison of the NGS results against Sanger sequencing data on a panel of clinical specimens, cell lines and European Molecular Genetics Quality Networks (EMQN) quality assurance samples showed 100% concordance in identifying pathogenic mutations. CONCLUSION With the capability of generating relatively higher throughput in a short time period, the NGS assay is a viable alternative to Sanger sequencing for detecting ATP7B mutations causally linked to Wilson disease in the clinical diagnostic laboratory.
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Abstract
CONTEXT Geographic distribution of ATP7B mutations in different populations. OBJECTIVE To summarise common mutations in the ATP7B gene and graphically illustrate their prevalence in different populations. METHODS A literature search was done using PubMed and the Wilson Disease Mutation Database (http://www.wilsondisease.med.ualberta.ca/database). RESULTS p.His1069Gln is the most prevalent mutation seen in Europe. In the Mediterranean countries, the array of prevalent mutations is different from the rest of Europe. In Far East Asian countries, the mutation p.Arg778Leu is the most common. In India, no single mutation seems to be dominant, owing to the vast ethnic diversity of the country. The p.Cys271* mutation is dominant in the east, west and south, but not reported in the north. In the Middle East, data from Saudi Arabia shows the p.Gln1399Arg mutation as the most prevalent. In the US, the p.His1069Gln is dominant, whereas in Brazil the mutation c.3402delC dominates. CONCLUSION Clinical features in WD patients can be misleading and often absent. Genetic testing is used to confirm the diagnosis. However, owing to the large gene size and vast diversity in the mutations, genetic testing can be time-consuming and tedious. This study reviews ATP7B mutations seen in different populations and can help develop time-saving methods and expediate the process of genetic analysis of WD.
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Affiliation(s)
- Amanda Gomes
- a Department of Dietetics and Nutrition , Harokopio University of Athens , Athens , Greece and.,b Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital & Medical Research Institute , Mumbai , India
| | - George V Dedoussis
- a Department of Dietetics and Nutrition , Harokopio University of Athens , Athens , Greece and
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Liu Y, Zhou H, Guo H, Bai Y. Genetic and Clinical Analysis in a Cohort of Patients with Wilson's Disease in Southwestern China. Arch Med Res 2015; 46:164-9. [PMID: 25704634 DOI: 10.1016/j.arcmed.2015.02.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 02/03/2015] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIMS Wilson's disease (WD), characterized by a disorder of copper metabolism, is an inherited autosomal recessive disease caused by mutations in the ATP7B gene. METHODS To explore genotype-phenotype correlations in Chinese WD patients and to evaluate the frequency of the ATP7B mutations, we described 77 clinically and biochemically confirmed WD patients and detected mutations in ten WD families from southwestern China. Clinical features were presented and all the exons of the ATP7B gene were screened. RESULTS The appearance of Kayser-Fleischer (K-F) rings was closely related to onset age, particularly before 10 years old. For those patients with predominantly neurological symptoms, MRI was the most sensitive and preferred examination. Eight mutations of the ATP7B gene were detected including seven reported mutations (c.2302dup, c.2304delC, c.2333 G>T, c.2621 C>T, c.2755 C>G, c.2975 C>T and c.1366 G>C) and four novel mutations (c.3446 G>A, c.3767insCA, c.3406 G>A and c.3700delG). c.2333 G>T was detected in 6/20 alleles (30%), accounting for the largest proportion, which could be regarded as a mutation hotspot in this region. CONCLUSIONS Our study extends the mutation spectrum of ATP7B and analyzes the relationship between mutations in the ATP7B gene and clinical findings of WD.
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Affiliation(s)
- Yu Liu
- Department of Medical Genetics, Third Military Medical University, Chongqing, P.R. China; The Second Battalion, Undergraduate Student Brigade, Third Military Medical University, Chongqing, P.R. China
| | - Hao Zhou
- Department of Medical Genetics, Third Military Medical University, Chongqing, P.R. China; The Second Battalion, Undergraduate Student Brigade, Third Military Medical University, Chongqing, P.R. China
| | - Hong Guo
- Department of Medical Genetics, Third Military Medical University, Chongqing, P.R. China.
| | - Yun Bai
- Department of Medical Genetics, Third Military Medical University, Chongqing, P.R. China
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Loss of COMMD1 and copper overload disrupt zinc homeostasis and influence an autism-associated pathway at glutamatergic synapses. Biometals 2014; 27:715-30. [DOI: 10.1007/s10534-014-9764-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 06/18/2014] [Indexed: 12/27/2022]
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Woimant F, Trocello JM, Chaine P, Broussolle E. Les Centres Maladies Rares en Neurologie ont-ils changé les pratiques et la prise en charge de la maladie de Wilson ? Rev Neurol (Paris) 2013; 169 Suppl 1:S18-22. [DOI: 10.1016/s0035-3787(13)70055-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- F Woimant
- Centre national de référence pour la Maladie de Wilson, Hôpital Lariboisière (APHP), 2 rue Ambroise Paré, 75010 Paris, France.
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Abstract
Wilson disease (WD) is an autosomal recessive inherited disease caused by abnormalities of the copper-transporting protein encoding gene ATP7B. In this study, we examined ATP7B for mutations in 114 individuals of Chinese Han population living in north China who were diagnosed as WD. Totally, we identified 36 mutations and 11 single-nucleotide polymorphisms (SNPs), of which 14 mutations have never been reported previously and 5 were firstly described in Chinese. Among these, p.R778L (21.5%), p.A874V (7.5%) and p.P992L (6.1%) were the most frequent mutations. A genotype of p.L770L+p.R778L+p.P992L was the most frequent triple mutations and two pairs of mutations, p.L770L/p.R778L and p.A874V/p.I929V, were closely related. In addition, a database was established to summarize all ATP7B mutations, including those reported previously and those identified in this study. Popular algorithms were used to predict the functional effects of these mutations, and finally, by comparative genomics approaches, we predicted a group of mutation hot spots for ATP7B. Our study will broaden our knowledge about ATP7B mutations in WD patients in north China, and be helpful for clinical genetic testing.
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