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Dmitriev OY, Patry J. Structure and mechanism of the human copper transporting ATPases: Fitting the pieces into a moving puzzle. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2024; 1866:184306. [PMID: 38408697 DOI: 10.1016/j.bbamem.2024.184306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 02/07/2024] [Accepted: 02/18/2024] [Indexed: 02/28/2024]
Abstract
Human copper transporters ATP7B and ATP7A deliver copper to biosynthetic pathways and maintain copper homeostasis in the cell. These enzymes combine several challenges for structural biology because they are large low abundance membrane proteins with many highly mobile domains and long disordered loops. No method has yet succeeded in solving the structure of the complete fully functional protein. Still, X-ray crystallography, Cryo-EM and NMR helped to piece together a structure based model of the enzyme activity and regulation by copper. We review the structures of ATP7B and ATP7A with an emphasis on the mechanistic insights into the unique aspects of the transport function and regulation of the human copper ATPases that have emerged from more than twenty years of research.
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Affiliation(s)
- Oleg Y Dmitriev
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada.
| | - Jaala Patry
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
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Chakraborty K, Das S, Pal A, Maji S, Rai B, Gupta A, Bhattacharjee A. Wilson disease-causing mutations in the carboxyl terminus of ATP7B regulates its localization and Golgi exit selectively in the unpolarized cells. Metallomics 2023; 15:mfad051. [PMID: 37660282 PMCID: PMC10506129 DOI: 10.1093/mtomcs/mfad051] [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: 03/22/2023] [Accepted: 08/06/2023] [Indexed: 09/04/2023]
Abstract
Mutational inactivation of the P-type Cu-ATPase ATP7B interferes with its cellular functions to varying extent leading to varied cellular phenotypes. Wilson's disease (WD) primarily affects organs composed of polarized/differentiated epithelial cells. Therefore, phenotypic variability might differ depending on the polarization/differentiation of the cells. The present study investigates the intracellular stability and localization of ATP7B harboring WD mutations in both unpolarized/undifferentiated and polarized/differentiated cell-based models. Green fluorescent protein (GFP)-ATP7B harboring the WD causing mutations, N41S, S653Y, R778Q, G1061E, H1069Q, S1423N, S1426I, and T1434M, are included for investigation. The C-terminal WD mutations (S1423N, S1426I, and T1434M), exhibit distinct localization and Cu(I) responsive anterograde and retrograde trafficking in undifferentiated/unpolarized vs. differentiated/polarized cells. While basal localization of the S1423N mutant gets corrected in the differentiated glia, its Cu(I) responsive anterograde and retrograde trafficking behavior is not identical to the wild-type. But localization and trafficking properties are completely rescued for the S1426I and T1434M mutants in the differentiated cells. Comprehensive meta-analysis on the effect of the reported C-terminal mutations on patient phenotype and cultured cells demonstrate discrete regions having distinct effects. While mutations in the proximal C-terminus affect ATP7B stability, the present study shows that the distal region dictates cell-specific Trans Golgi Network (TGN) localization and exit. The localization and export properties are corrected in the differentiated cells, which is a plausible mechanism for the milder phenotype exhibited by these mutations. It highlights the critical role of the C-terminus in cell-specific TGN retention and exit of ATP7B.
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Affiliation(s)
| | - Santanu Das
- Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, India
| | - Anusree Pal
- Amity Institute of Biotechnology, Amity University, Kolkata, India
| | - Saptarshi Maji
- Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, India
| | - Bhawana Rai
- Amity Institute of Biotechnology, Amity University, Kolkata, India
| | - Arnab Gupta
- Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, India
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Lorente-Arencibia P, García-Villarreal L, González-Montelongo R, Rubio-Rodríguez LA, Flores C, Garay-Sánchez P, delaCruz T, Santana-Verano M, Rodríguez-Esparragón F, Benitez-Reyes JN, Fernández-Fuertes F, Tugores A. Wilson Disease Prevalence: Discrepancy Between Clinical Records, Registries and Mutation Carrier Frequency. J Pediatr Gastroenterol Nutr 2022; 74:192-199. [PMID: 34620762 DOI: 10.1097/mpg.0000000000003322] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Diagnosis of Wilson disease (WD) is difficult and, as early detection may prevent all symptoms, it is essential to know the exact prevalence to evaluate the cost-efficacy of a screening program. As the number of WD patients was high in our population, we wished to estimate prevalence by determining the carrier frequency for clinically relevant ATP7B mutations. METHODS To estimate prevalence, screening for the most prevalent mutation was performed in 1661 individuals with ancestry in Gran Canaria, and the frequency of other mutations was estimated from patient records. Alternatively, ATP7B mutations were detected from exomes and genomes from 851 individuals with Canarian ancestry, 236 from Gran Canaria, and a public Spanish exome database. RESULTS Estimated carrier frequencies in Gran Canaria ranged from 1 in 20 to 28, depending on the method used, resulting in prevalences of 1 case per 1547 to 3140 inhabitants. Alternatively, the estimated affected frequencies were 1 in 5985 to 7980 and 1 in 6278 to 16,510 in the archipelago or mainland Spain respectively. CONCLUSIONS The number of carriers predicts much higher prevalences than reported, suggesting that WD is underdiagnosed; specific mutations may remain unnoticed due to low penetrance or no signs of disease at all; regional prevalence rather than national prevalence should be considered in cost-efficacy models to approach preventive screening in the asymptomatic population and genetic screening strategies will have to deal with the genetic heterogeneity of ATP7B in the general population and in patients.
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Affiliation(s)
- Pascual Lorente-Arencibia
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de GC
| | - Luis García-Villarreal
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de GC
| | - Rafaela González-Montelongo
- Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER)
- Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna
| | | | - Carlos Flores
- Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER)
- Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna
- Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerif
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid
| | - Paloma Garay-Sánchez
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de GC
| | - Tanausú delaCruz
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de GC
| | - Milagros Santana-Verano
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de GC
| | | | - Juana N Benitez-Reyes
- Department of Haematology, Complejo Hospitalario Universitario Insular Materno-Infantil, Spain
| | | | - Antonio Tugores
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de GC
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Molina Romero M, Yoldi Chaure A, Gañán Parra M, Navas Bastida P, del Pico Sánchez JL, Vaquero Argüelles Á, de la Fuente Vaquero P, Ramírez López JP, Castilla Alcalá JA. Probability of high-risk genetic matching with oocyte and semen donors: complete gene analysis or genotyping test? J Assist Reprod Genet 2022; 39:341-355. [PMID: 35091964 PMCID: PMC8956772 DOI: 10.1007/s10815-021-02381-0] [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: 03/29/2021] [Accepted: 12/17/2021] [Indexed: 02/03/2023] Open
Abstract
PURPOSE To estimate the probability of high-risk genetic matching when assisted reproductive techniques (ART) are applied with double gamete donation, following an NGS carrier test based on a complete study of the genes concerned. We then determine the results that would have been obtained if the genotyping tests most widely used in Spanish gamete banks had been applied. METHODS In this descriptive observational study, 1818 gamete donors were characterised by NGS. The pathogenic variants detected were analysed to estimate the probability of high-risk genetic matching and to determine the results that would have been obtained if the three most commonly used genotyping tests in ART had been applied. RESULTS The probability of high-risk genetic matching with gamete donation, screened by NGS and complete gene analysis, was 5.5%, versus the 0.6-2.7% that would have been obtained with the genotyping test. A total of 1741 variants were detected, including 607 different variants, of which only 22.6% would have been detected by all three genotyping tests considered and 44.7% of which would not have been detected by any of these tests. CONCLUSION Our study highlights the considerable heterogeneity of the genotyping tests, which present significant differences in their ability to detect pathogenic variants. The complete study of the genes by NGS considerably reduces reproductive risks when genetic matching is performed with gamete donors. Accordingly, we recommend that carrier screening in gamete donors be carried out using NGS and a complete study with nontargeted analysis of the variants of the screened genes.
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Affiliation(s)
- Marta Molina Romero
- CEIFER Biobanco - NextClinics, Calle Maestro Bretón, 1, 18004 Granada, Spain
| | | | | | | | | | | | | | | | - José Antonio Castilla Alcalá
- CEIFER Biobanco - NextClinics, Calle Maestro Bretón, 1, 18004 Granada, Spain ,U. Reproducción, UGC Obstetricia y Ginecología, HU Virgen de Las Nieves, Granada, Spain ,Instituto de Investigación Biosanitaria Ibs.Granada, Granada, Spain
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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: 79] [Impact Index Per Article: 19.8] [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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Das S, Maji S, Ruturaj, Bhattacharya I, Saha T, Naskar N, Gupta A. Retromer retrieves the Wilson disease protein ATP7B from endolysosomes in a copper-dependent manner. J Cell Sci 2020; 133:jcs246819. [PMID: 33268466 PMCID: PMC7611186 DOI: 10.1242/jcs.246819] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 11/19/2020] [Indexed: 12/31/2022] Open
Abstract
The Wilson disease protein, ATP7B maintains copper (herein referring to the Cu+ ion) homeostasis in the liver. ATP7B traffics from trans-Golgi network to endolysosomes to export excess copper. Regulation of ATP7B trafficking to and from endolysosomes is not well understood. We investigated the fate of ATP7B after copper export. At high copper levels, ATP7B traffics primarily to acidic, active hydrolase (cathepsin-B)-positive endolysosomes and, upon subsequent copper chelation, returns to the trans-Golgi network (TGN). At high copper, ATP7B colocalizes with endolysosomal markers and with a core member of retromer complex, VPS35. Knocking down VPS35 did not abrogate the copper export function of ATP7B or its copper-responsive anterograde trafficking to vesicles; rather upon subsequent copper chelation, ATP7B failed to relocalize to the TGN, which was rescued by overexpressing wild-type VPS35. Overexpressing mutants of the retromer complex-associated proteins Rab7A and COMMD1 yielded a similar non-recycling phenotype of ATP7B. At high copper, VPS35 and ATP7B are juxtaposed on the same endolysosome and form a large complex that is stabilized by in vivo photoamino acid labeling and UV-crosslinking. We demonstrate that retromer regulates endolysosome to TGN trafficking of copper transporter ATP7B in a manner that is dependent upon intracellular copper.
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Affiliation(s)
- Santanu Das
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
| | - Saptarshi Maji
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
| | - Ruturaj
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
| | - Indira Bhattacharya
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
| | - Tanusree Saha
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
| | - Nabanita Naskar
- Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
| | - Arnab Gupta
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
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Yi F, Poskanzer SA, Myers CT, Thies J, Collins CJ, Dayuha R, Duong P, Houwen R, Hahn SH. p.P1379S, a benign variant with reduced ATP7B protein level in Wilson Disease. JIMD Rep 2020; 54:32-36. [PMID: 32685348 PMCID: PMC7358663 DOI: 10.1002/jmd2.12127] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 04/20/2020] [Accepted: 04/23/2020] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Wilson disease (WD) is an autosomal recessive disorder of copper transport caused by inherited defects in the ATP7B gene and results in toxic accumulation of copper in various organs. We previously reported a family with three consecutive generations affected by WD that carries the variant, p.P1379S, which was classified at the time as likely pathogenic. However, recent investigations of the p.P1379S variant indicate a possible conflict of interpretations regarding its pathogenicity. This led us to explore the quantification of ATP7B in dried blood spots (DBS) using a surrogate peptide to study the effects of the p.P1379S variant on ATP7B concentrations in two unrelated families with the common p.P1379S variant. METHODS AND RESULTS ATP7B was quantified using the peptide immunoaffinity enrichment coupled with selected reaction monitoring mass spectrometry (immuno-SRM) method which utilizes antibody-mediated peptide capture from DBS. Two patients affected with WD had undetectable ATP7B level while four compound heterozygous children with one known pathogenic variant and the p.P1379S had significantly reduced ATP7B levels. Of note, all four children remain asymptomatic without abnormal laboratory consequences despite being untreated for WD. CONCLUSION These two families demonstrated that p.P1379S, when compounded with two known pathogenic variants, resulted in significantly reduced protein levels but retained enough function to maintain normal copper homeostasis. This implies that p.P1379S is benign in nature. A better understanding of the nature and consequences of variants in WD will help in informing patient care and avoiding unnecessary treatments.
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Affiliation(s)
- Fan Yi
- Seattle Children's Research InstituteSeattleWashingtonUSA
| | - Sheri A. Poskanzer
- Department of PediatricsUniversity of Washington, School of MedicineSeattleWashingtonUSA
| | - Candace T. Myers
- Department of LaboratoriesSeattle Children's HospitalSeattleWashingtonUSA
| | - Jenny Thies
- Biochemical GeneticsSeattle Children's HospitalSeattleWashingtonUSA
| | | | | | - Phi Duong
- Seattle Children's Research InstituteSeattleWashingtonUSA
| | - Roderick Houwen
- Wilhelmina Children's Hospital, Utrecht UniversityUtrechtNetherlands
| | - Si Houn Hahn
- Seattle Children's Research InstituteSeattleWashingtonUSA
- Department of PediatricsUniversity of Washington, School of MedicineSeattleWashingtonUSA
- Biochemical GeneticsSeattle Children's HospitalSeattleWashingtonUSA
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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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The global prevalence of Wilson disease from next-generation sequencing data. Genet Med 2018; 21:1155-1163. [PMID: 30254379 DOI: 10.1038/s41436-018-0309-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 09/05/2018] [Indexed: 12/16/2022] Open
Abstract
PURPOSE Wilson disease (WD) is an autosomal recessive disorder of copper metabolism, caused by pathogenic variants in ATP7B. We aimed to (1) perform a meta-analysis of previous WD prevalence estimates, (2) estimate the prevalence of WD from population sequencing data, and (3) generate an ATP7B gene variant database. METHODS MEDLINE and EMBASE were systematically searched. Previous prevalence estimates were subjected to meta-analysis. All previously reported pathogenic ATP7B variants were compiled and annotated with gnomAD allele frequencies. Pooled global and ethnicity-specific genetic prevalences for WD were generated using the Hardy-Weinberg equation. RESULTS Meta-analysis of genetic studies of WD prevalence gave an estimate 12.7 per 100,000 (95% confidence interval [CI]: 6.3-23.0). We developed a referenced, searchable ATP7B database comprising 11,520 variants including 782 previously reported disease variants, which can be found at http://www.wilsondisease.tk/ ; 216/782 of these were present in gnomAD, remained after filtering by allele frequency, and met American College of Medical Genetics and Genomics criteria. Based on these, the genetic prevalence of WD was 13.9 per 100,000 (95% CI: 12.9-14.9), or 1 per 7194. Combining this with 60 predicted pathogenic variants gave a birth prevalence of 15.4 per 100,000 (95% CI: 14.4-16.5). CONCLUSION The genetic prevalence of Wilson disease may be greater than previous estimates.
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Kumari N, Kumar A, Thapa BR, Modi M, Pal A, Prasad R. Characterization of mutation spectrum and identification of novel mutations in ATP7B gene from a cohort of Wilson disease patients: Functional and therapeutic implications. Hum Mutat 2018; 39:1926-1941. [PMID: 30120852 DOI: 10.1002/humu.23614] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 08/09/2018] [Accepted: 08/13/2018] [Indexed: 12/13/2022]
Abstract
Wilson disease (WD), a copper metabolism disorder, occurs due to the presence of mutations in the gene encoding ATP7B, a protein that primarily facilitates hepatic copper excretion. A better understanding of spectrum and functional significance of ATP7B variants is critical to formulating targeted and personalized therapies. Henceforth, we screened and sequenced 21 exons of ATP7B gene from 50 WD patients and 60 healthy subjects. We identified 28 variants comprising, seven novels in 20% alleles, while eight variations affecting 23% alleles were first time reported in Indian cohort. The c.813C>A, p.(Cys271*) (10%) was the most frequent mutation. Bioinformatics analysis revealed five of seven novel variants viz. c.1600C>A, p.(Pro534Thr); c.1616C>A, p.(Pro539His); c.1924G>T, p.(Asp642Tyr); c.2168G>C, p.(Arg723Thr); c.2174G>C, p.(Arg725Thr) resulted in protein misfolding. Sequence conservation analysis of ATP7B regions containing novel variants documented an evolutionarily conserved nature. Functional analysis of these novel variants in five different cell lines lacking inherent ATP7B expression demonstrated sensitivity to CuCl2 -treatment, experiencing augmented cellular copper retention and decreased copper excretion as well as ceruloplasmin secretion to that of wildtype-ATP7B expressing cells. Interestingly, pharmacological chaperone 4-phenylbutyrate, a clinically approved compound, partially restored protein function of ATP7B mutants. These findings might enable novel treatment strategies in WD by clinically enhancing the protein expression of mutant ATP7B with residual copper export activity.
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Affiliation(s)
- Niti Kumari
- Department of Biochemistry, PGIMER, Chandigarh, India
| | - Aman Kumar
- Department of Biochemistry, PGIMER, Chandigarh, India
| | - Babu Ram Thapa
- Department of Paediatrics Gastroenterology, PGIMER, Chandigarh, India
| | - Manish Modi
- Department of Neurology, PGIMER, Chandigarh, India
| | - Arnab Pal
- Department of Biochemistry, PGIMER, Chandigarh, India
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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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Gupta A, Das S, Ray K. A glimpse into the regulation of the Wilson disease protein, ATP7B, sheds light on the complexity of mammalian apical trafficking pathways. Metallomics 2018; 10:378-387. [PMID: 29473088 DOI: 10.1039/c7mt00314e] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Wilson disease (WD), a Mendelian disorder of copper metabolism caused by mutations in the ATP7B gene, manifests a large spectrum of phenotypic variability. This phenomenon of extensive symptom variation is not frequently associated with a monogenic disorder. We hypothesize that the phenotypic variability in WD is primarily driven by the variations in interacting proteins that regulate the ATP7B function and localization in the cell. Based on existing literature, we delineated a potential molecular mechanism for ATP7B mediated copper transport in the milieu of its interactome, its dysfunction in WD and the resulting variability in the phenotypic manifestation. Understanding the copper-induced apical trafficking of ATP7B also significantly contributes to the appreciation of the complexities of the ligand-induced transport pathway. We believe that this holistic view of WD will pave the way for a better opportunity for rational drug design and therapeutics.
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Affiliation(s)
- Arnab Gupta
- Department of Biological Sciences, Indian Institute of Science Education and Research - Kolkata (IISER K), Mohanpur 741246, West Bengal, India.
| | - Santanu Das
- Department of Biological Sciences, Indian Institute of Science Education and Research - Kolkata (IISER K), Mohanpur 741246, West Bengal, India.
| | - Kunal Ray
- Academy of Scientific & Innovative Research (AcSIR), CSIR - HRDC Campus, Ghaziabad, Uttar Pradesh - 201002, India
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Zarina A, Tolmane I, Kreile M, Chernushenko A, Cernevska G, Pukite I, Micule I, Krumina Z, Krumina A, Rozentale B, Piekuse L. Genetic variation spectrum in ATP7B gene identified in Latvian patients with Wilson disease. Mol Genet Genomic Med 2017; 5:405-409. [PMID: 28717664 PMCID: PMC5511797 DOI: 10.1002/mgg3.297] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 04/14/2017] [Accepted: 04/17/2017] [Indexed: 12/27/2022] Open
Abstract
Background Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by allelic variants in ATP7B gene. More than 500 distinct variants have been reported, the most common WD causing allelic variant in the patients from Central, Eastern, and Northern Europe is H1069Q. Methods All Latvian patients with clinically confirmed WD were screened for the most common mutation p.H1069Q by PCR Bi‐PASA method. Direct DNA sequencing of gene ATP7B (all 21 exons) was performed for the patients with WD symptoms, being either heterozygous for H1069Q or without it on any allele. Results We identified 15 different allelic variants along with eight non‐disease‐causing allelic variants. Based on the gene molecular analysis and patients' clinical data variant p.His1069Gln was found in 66.9% of WD alleles. Wide clinical variability was observed among individuals with the same ATP7B genotype. The results of our study confirm that neurological manifestations of WD are typically present later than the liver disease but no significant association between the presence/absence of the most common genetic variant and mode of initial WD presentation or age at presentation was identified. Conclusions (1) The most prevalent mutation in Latvian patients with Wilson disease was c.3207C>A (p.His1069Gln); (2) No significant phenotype–genotype correlation was found in Latvian patients with Wilson disease; (3) The estimated prevalence of Wilson disease in Latvia is 1 of 24,000 cases which is higher than frequently quoted prevalence of 1: 30,000.
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Affiliation(s)
- Agnese Zarina
- Scientific Laboratory of Molecular GeneticsRīga Stradiņš UniversityRigaLatvia
| | - Ieva Tolmane
- Riga East Clinical University Hospitalstationary "Latvian Centre of Infectious Diseases"RigaLatvia.,Faculty of MedicineUniversity of LatviaRigaLatvia
| | - Madara Kreile
- Scientific Laboratory of Molecular GeneticsRīga Stradiņš UniversityRigaLatvia
| | - Aleksandrs Chernushenko
- Riga East Clinical University Hospitalstationary "Latvian Centre of Infectious Diseases"RigaLatvia
| | | | - Ieva Pukite
- Children's Clinical University HospitalRigaLatvia
| | - Ieva Micule
- Children's Clinical University HospitalRigaLatvia
| | - Zita Krumina
- Children's Clinical University HospitalRigaLatvia
| | - Astrida Krumina
- Scientific Laboratory of Molecular GeneticsRīga Stradiņš UniversityRigaLatvia
| | - Baiba Rozentale
- Riga East Clinical University Hospitalstationary "Latvian Centre of Infectious Diseases"RigaLatvia
| | - Linda Piekuse
- Scientific Laboratory of Molecular GeneticsRīga Stradiņš UniversityRigaLatvia
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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: 16] [Impact Index Per Article: 2.0] [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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16
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Wachsmann J, Peng F. Molecular imaging and therapy targeting copper metabolism in hepatocellular carcinoma. World J Gastroenterol 2016; 22:221-231. [PMID: 26755872 PMCID: PMC4698487 DOI: 10.3748/wjg.v22.i1.221] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 10/18/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Significant efforts have been devoted to identify new biomarkers for molecular imaging and targeted therapy of HCC. Copper is a nutritional metal required for the function of numerous enzymatic molecules in the metabolic pathways of human cells. Emerging evidence suggests that copper plays a role in cell proliferation and angiogenesis. Increased accumulation of copper ions was detected in tissue samples of HCC and many other cancers in humans. Altered copper metabolism is a new biomarker for molecular cancer imaging with position emission tomography (PET) using radioactive copper as a tracer. It has been reported that extrahepatic mouse hepatoma or HCC xenografts can be localized with PET using copper-64 chloride as a tracer, suggesting that copper metabolism is a new biomarker for the detection of HCC metastasis in areas of low physiological copper uptake. In addition to copper modulation therapy with copper chelators, short-interference RNA specific for human copper transporter 1 (hCtr1) may be used to suppress growth of HCC by blocking increased copper uptake mediated by hCtr1. Furthermore, altered copper metabolism is a promising target for radionuclide therapy of HCC using therapeutic copper radionuclides. Copper metabolism has potential as a new theranostic biomarker for molecular imaging as well as targeted therapy of HCC.
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17
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Cocoş R, Şendroiu A, Schipor S, Bohîlţea LC, Şendroiu I, Raicu F. Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson's disease: genetic and clinical homogeneity. PLoS One 2014; 9:e98520. [PMID: 24897373 PMCID: PMC4045667 DOI: 10.1371/journal.pone.0098520] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Accepted: 04/29/2014] [Indexed: 12/12/2022] Open
Abstract
Wilson’s disease is an autosomal recessive disorder caused by more than 500 mutations in ATP7B gene presenting considerably clinical manifestations heterogeneity even in patients with a particular mutation. Previous findings suggested a potential role of additional genetic modifiers and environment factors on phenotypic expression among the affected patients. We conducted clinical and genetic investigations to perform genotype-phenotype correlation in two large families living in a socio-culturally isolated community with the highest prevalence of Wilson’s disease ever reported of 1∶1130. Sequencing of ATP7B gene in seven affected individuals and 43 family members identified a common compound heterozygous genotype, H1069Q/M769H-fs, in five symptomatic and two asymptomatic patients and detected the presence of two out of seven identified single nucleotide polymorphisms in all affected patients. Symptomatic patients had similar clinical phenotype and age at onset (18±1 years) showing dysarthria and dysphagia as common clinical features at the time of diagnosis. Moreover, all symptomatic patients presented Kayser-Fleischer rings and lack of dystonia accompanied by unfavourable clinical outcomes. Our findings add value for understanding of genotype-phenotype correlations in Wilson’s disease based on a multifamily study in an isolated population with high extent of genetic and environmental homogeneity as opposed to majority of reports. We observed an equal influence of presumed other genetic modifiers and environmental factors on clinical presentation and age at onset of Wilson’s disease in patients with a particular genotype. These data provide valuable inferences that could be applied for predicting clinical management in asymptomatic patients in such communities.
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Affiliation(s)
- Relu Cocoş
- Chair of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Genome Life Research Centre, Bucharest, Romania
| | | | - Sorina Schipor
- National Institute of Endocrinology “C. I. Parhon”, Bucharest, Romania
| | - Laurenţiu Camil Bohîlţea
- Chair of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Sf. Pantelimon Clinical Emergency Hospital, Bucharest, Romania
| | | | - Florina Raicu
- Chair of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Francisc I. Rainer Anthropological Research Institute, Romanian Academy, Bucharest, Romania
- * E-mail:
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18
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Bennett JT, Schwarz KB, Swanson PD, Hahn SH. An exceptional family with three consecutive generations affected by Wilson disease. JIMD Rep 2013; 10:1-4. [PMID: 23430806 DOI: 10.1007/8904_2012_206] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Revised: 11/27/2012] [Accepted: 12/07/2012] [Indexed: 10/27/2022] Open
Abstract
Wilson disease (WD) is a disorder of copper transport that can cause hepatic and neuropsychiatric symptoms. Because of its broad spectrum of clinical manifestations that can present in almost any decade of life, a high degree of clinical suspicion is needed for diagnosis. We present an exceptional family with three consecutive generations affected by WD. Autosomal recessive disorders are not typically present in consecutive generations, but this can occur, particularly when carrier frequencies are as high as in WD. This point is of critical importance in counseling families affected by WD. This case also highlights the importance of genetic testing in confirming the diagnosis of WD, particularly when there is a positive family history. To our knowledge, this is the first report of WD in three consecutive generations.
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Affiliation(s)
- James T Bennett
- Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, USA
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19
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Bost M, Piguet-Lacroix G, Parant F, Wilson CMR. Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis. J Trace Elem Med Biol 2012; 26:97-101. [PMID: 22677543 DOI: 10.1016/j.jtemb.2012.04.024] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Accepted: 04/20/2012] [Indexed: 10/28/2022]
Abstract
ATP7B mutations result in Cu storage in the liver and brain in Wilson disease (WD). Atox1 and COMMD1 were found to interact with ATP7B and involved in copper transport in the hepatocyte. To understand the molecular etiology of WD, we analyzed ATP7B, Atox1 and COMMD1 genes. Direct sequencing of (i) ATP7B gene was performed in 112 WD patients to identify the spectrum of disease-causing mutations in the French population, (ii) Atox1 gene was performed to study the known polymorphism 5'UTR-99T>C in 78 WD patients with two ATP7B mutations and (iii) COMMD1 gene was performed to detect the nucleotide change c.492GAT>GAC. MLPA (Multiplex Ligation-dependent Probe Amplification) analysis was performed in WD patients presenting only one ATP7B mutation. Among our 112 WD unrelated patients, 83 different ATP7B gene mutations were identified, 27 of which were novel. Two ATP7B mutations were identified in 98 WD cases, and one mutation was identified in 14 cases. In two of these 14 WD patients, we identified the deletion of exon 4 of the ATP7B gene by MLPA technique. In 78 selected patients of the cohort with two mutations in ATP7B, we have examined genotype-phenotype correlation between the detected changes in Atox1 and COMMD1 genes, and the presentation of the WD patients. Based on the data of this study, no major role can be attributed to Atox1 and COMMD in the pathophysiology or clinical variation of WD.
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Affiliation(s)
- Muriel Bost
- Centre de Biologie et Pathologie Est, Laboratoire des Maladies Héréditaires du Métabolisme, 59 Boulevard Pinel, 69677 Bron cedex, France.
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20
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Luoma LM, Deeb TM, Macintyre G, Cox DW. Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B. Hum Mutat 2010; 31:569-77. [DOI: 10.1002/humu.21228] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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21
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Rodriguez-Granillo A, Crespo A, Wittung-Stafshede P. Conformational Dynamics of Metal-Binding Domains in Wilson Disease Protein: Molecular Insights into Selective Copper Transfer. Biochemistry 2009; 48:5849-63. [DOI: 10.1021/bi900235g] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
| | - Alejandro Crespo
- Department of Bioengineering, Rice University, Houston, 77005 Texas
| | - Pernilla Wittung-Stafshede
- Department of Biochemistry and Cell Biology, Rice University, Houston, 77251 Texas
- Department of Chemistry, Umeå University, 901 87 Umeå, Sweden
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22
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Mak CM, Lam CW. Diagnosis of Wilson's disease: a comprehensive review. Crit Rev Clin Lab Sci 2008; 45:263-90. [PMID: 18568852 DOI: 10.1080/10408360801991055] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Wilson's disease is an autosomal recessive disorder of copper metabolism. The culprit gene is ATP7B. The worldwide prevalence is about 1 in 30,000, which may vary by population. Higher prevalence rates were reported using more sensitive screening techniques and pilot population screening. Typical presentations include neuropsychiatric and hepatic dysfunction, whereas atypical presentations are protean. Diagnosis relies on a high clinical suspicion, typical neurological symptoms, presence of Kayser-Fleischer rings, and reduced serum ceruloplasmin concentration. The conventional value of < 0.20 g/l is not a universal diagnostic value. Age of the subjects and analytical variations should be considered when interpreting these levels. Patients with inconclusive findings require further investigations such as 24 h urinary free-copper excretion, penicillamine challenge test, liver copper measurement, and detection of gene mutations. Direct molecular diagnosis remains the most decisive tool. Other tests such as non-ceruloplasmin-bound copper are unreliable. Potential pitfalls and limitations of these diagnostic markers are critically reviewed in this paper. The mainstays of therapy are trientine, penicillamine, and/or zinc. Liver transplantation is lifesaving for those with advanced disease. Ceruloplasmin oxidase activity and serum free-copper concentration should be monitored in patients on long-term de-coppering therapy to prevent iatrogenic copper deficiency.
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Affiliation(s)
- Chloe M Mak
- Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
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23
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Davies LP, Macintyre G, Cox DW. New mutations in the Wilson disease gene, ATP7B: implications for molecular testing. ACTA ACUST UNITED AC 2008; 12:139-45. [PMID: 18373411 DOI: 10.1089/gte.2007.0072] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Wilson disease (WND), an autosomal recessive disorder of copper transport with a broad range of genotypic and phenotypic characteristics, results from mutations in the ATP7B gene. ATP7B encodes a copper transporting P-type ATPase involved in the transport of copper into the plasma protein ceruloplasmin, and for excretion of copper from the liver. Defects in ATP7B lead to copper storage in liver, brain and kidney. Mutation analysis was carried out on 300 WND patients of various origins, and new mutations not previously reported were identified: European white (p.L217X, c.918_931, c.1073delG, c.3082_3085delAAGAinsCG, p.V536A, p.S657R, p.A971V, p.T974M, p.Q1004P, p.D1164N, p.E1173G, p.I1230V, p.M1359I, c.2355+4A>G), Sephardic Jewish (p.Q286X), Filipino (p.G1149A), Lebanese (p.R1228T), Japanese (p.D1267V) and Taiwanese (p.A1328T). All but one missense variant have strong evidence for classification as disease-causing mutations. In the patients reported here, we also identified 20 nucleotide substitutions, six not previously reported, which cause silent amino acid changes or intronic changes. Documentation and characterization of all variants is essential for accurate DNA diagnosis in WND because of the wide range of clinical and biochemical variability.
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Affiliation(s)
- Lisa Prat Davies
- Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
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Hsi G, Cullen LM, Macintyre G, Chen MM, Glerum DM, Cox DW. Sequence variation in the ATP-binding domain of the Wilson disease transporter, ATP7B, affects copper transport in a yeast model system. Hum Mutat 2008; 29:491-501. [PMID: 18203200 DOI: 10.1002/humu.20674] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
ATP7B is a copper transporting P-type ATPase defective in the autosomal recessive copper storage disorder, Wilson disease (WND). Functional assessment of variants helps to distinguish normal from disease-causing variants and provides information on important amino acid residues. A total of 11 missense variants of ATP7B, originally identified in WND patients, were examined for their capacity to functionally complement a yeast mutant strain in which the yeast gene ortholog, CCC2, was disrupted. Solution structures of ATP7B domains were used to predict the effects of each variant on ATP7B structure. Three variants lie within the copper-binding domain and eight within the ATP-binding domain of ATP7B. All three ATP7B variants within the copper-binding domain and four within the ATP-binding domain showed full complementation of the yeast ccc2 phenotype. For the remaining four located in the ATP-binding domain, p.Glu1064Lys and p.Val1106Asp were unable to complement the yeast ccc2 high-affinity iron uptake deficiency phenotype, apparently due to mislocalization and/or change in conformation of the variant protein. p.Leu1083Phe exhibited a temperature-sensitive phenotype with partial complementation at 30 degrees C and a severe deficit at 37 degrees C. p.Met1169Val only partially complemented the ccc2 phenotype at 30 degrees C and 37 degrees C. Therefore, four variant positions were identified as important for copper transport and as disease-causing changes. Since the yeast assay specifically evaluates copper transport function, variants with normal transport could be defective in some other aspect of ATP7B function, particularly trafficking in mammalian cells. Functional assessment is critical for reliable use of mutation analysis as an aid to diagnosis of this clinically variable condition.
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Affiliation(s)
- Gloria Hsi
- Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
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Kenney SM, Cox DW. Sequence variation database for the Wilson disease copper transporter, ATP7B. Hum Mutat 2008; 28:1171-7. [PMID: 17680703 DOI: 10.1002/humu.20586] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Wilson disease (WND) is a disorder of copper transport resulting in copper accumulation in liver, kidney, and brain. This recessive disorder expresses variable clinical symptoms affecting liver, brain, and/or kidney. The age of onset of symptoms varies from 3 to almost 70 years, so the diagnosis for this treatable disorder is easily missed. The defective gene is a membrane P-type ATPase, with similar structure to the other metal transporting ATPases. Most patients with Wilson disease are compound heterozygotes. This report describes the database we have developed for reporting of mutations in ATP7B, the gene defective in WND. The database includes more than 518 variants (379 probable disease-causing and the remainder possible normal variants) from populations worldwide (Available at: www.medicalgenetics.med.ualberta.ca/wilson/index.php; Last accessed: 20 June 2007). The tables in this database are a valuable resource for the study of population variation and the function of the transporter, and will assist in the identification of disease and non-disease-causing sequence variants.
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Affiliation(s)
- Susan M Kenney
- Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
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Xuan A, Bookman I, Cox DW, Heathcote J. Three atypical cases of Wilson disease: assessment of the Leipzig scoring system in making a diagnosis. J Hepatol 2007; 47:428-33. [PMID: 17629589 DOI: 10.1016/j.jhep.2007.05.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2007] [Accepted: 05/24/2007] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS The diagnosis of this condition in the absence of any neurological findings may pose a dilemma. In 2001, experts from The 8th International Conference on Wilson disease (WD) and Menkes disease in Leipzig, Germany proposed a scoring system that may facilitate diagnosis of WD. METHODS/RESULTS Three patients were identified as having an atypical presentation of WD as they all presented after the age 40. Two of the three presented with established cirrhosis, and none had any neuropsychiatric manifestations. All three patients fulfilled the Leipzig diagnostic criteria proposed by EASL prior to confirmatory mutation analysis. Patient A died of liver failure despite treatment. Patients B and C have remained with stable liver disease on chelation therapy. CONCLUSIONS We believe these patients represent a group most likely to be missed in the diagnostic work-up of liver disease due to a combination of atypical features such as older age of onset, presence of other confounders for liver disease, and sometimes absence of Kayser-Fleischer rings. The Leipzig scoring system proposed in 2003 was helpful in support of an initial diagnosis of Wilson disease in these patients, validated later by genetic testing.
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Affiliation(s)
- Andy Xuan
- Department of Medicine, McMaster University, Hamilton, ON, Canada L8N 3Z5.
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Chappuis P, Callebert J, Quignon V, Woimant F, Laplanche JL. Late neurological presentations of Wilson disease patients in French population and identification of 8 novel mutations in the ATP7B gene. J Trace Elem Med Biol 2007; 21:37-42. [PMID: 17317524 DOI: 10.1016/j.jtemb.2006.11.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2006] [Accepted: 11/12/2006] [Indexed: 01/28/2023]
Abstract
Wilson disease (WD) is an autosomal recessive disorder of copper biliary excretion caused by an impaired function of ATP7B, a metal-transporting P-type ATPase encoded by WD gene. It results in copper accumulation, mostly in liver and brain tissues. Mutation analysis was carried out on 11 WD French unrelated patients presenting a predominant neurological form of this illness. SSCP and dHPLC analysis followed by sequencing of the 21 exons and their flanking introns were performed. Thirteen different mutations in a total of 17, and, among them, 10 novel variants were evidenced. Two deletions (c.654_655delCC and c.1745_1746delTA), 4 missense mutations (p.F763Y, p.G843R, p.D918A and p.L979Q), 1 nonsense mutation (p.Q1200X), 1 splice site mutation (c.1947-1G>C) and 2 intronic silent substitutions (c.2448-25G>T and c.3412+13T>A) were detected. These data extend the mutational spectrum of the disease, already known to be a very heterogeneous genetic disorder. As compared to hepatic manifestations, the phenotypes associated to these mutations confirm that neurological presentations associated with other mutations than p.H1069Q are also often late in their onset. Most of these neurological forms probably correspond to an attenuated impairment of copper metabolism, as compared to hepatic forms of the disease, mostly diagnosed earlier.
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Affiliation(s)
- Philippe Chappuis
- Hôpital Lariboisière, Centre National Référence Bernard Pépin pour la Maladie de Wilson, Service de Biochimie et Biologie Moléculaire, 2, rue A. Paré, 75475 Paris Cedex 10, France.
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