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Mata M, Tabbara MM, Alvarez A, Chandar J, Defreitas M, Ciancio G. Case series of kidney transplantation in two pediatric recipients with rare genetic diseases and intellectual disability. BMC Pediatr 2024; 24:823. [PMID: 39696129 DOI: 10.1186/s12887-024-05304-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 12/02/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Kidney transplantation is the gold standard treatment for end-stage kidney disease in children. Rare genetic systemic diseases associated with cystic kidney disease such as COL4A1-related disorder and oral facial digital syndrome type 1 could contribute to end-stage kidney disease in the pediatric population but there is scarce evidence in the literature regarding kidney transplant outcomes in these cases. CASE PRESENTATION We report a case of a 5-year-old male with COL4A1-related disorder who received a living-related donor kidney transplant from his mother. To our knowledge this is the first reported kidney transplant in a pediatric recipient with COL4A1-related disorder. We also present a case of a 16-year-old female with oral facial digital syndrome type 1 who received a deceased donor kidney transplant. CONCLUSIONS In this case series, we discuss surgical technique, indication for kidney transplant, influence of comorbidities and intellectual disability in transplant outcomes.
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Affiliation(s)
- Marina Mata
- Department of Surgery, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA
- Miami Transplant Institute, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA
- Unidad de Cirugia Renal, Trasplante e Investigación, Hospital Ramón y Cajal, Madrid, Spain
| | - Marina M Tabbara
- Department of Surgery, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA
- Miami Transplant Institute, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA
| | - Angel Alvarez
- Miami Transplant Institute, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA
| | - Jayanthi Chandar
- Divison of Pediatric Nephrology, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA
| | - Marissa Defreitas
- Divison of Pediatric Nephrology, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA
| | - Gaetano Ciancio
- Department of Surgery, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA.
- Miami Transplant Institute, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA.
- Department of Surgery and Urology, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA.
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Mori T, Fujimaru T, Liu C, Patterson K, Yamamoto K, Suzuki T, Chiga M, Sekine A, Ubara Y, Miller DE, Zalusky MP, Mandai S, Ando F, Mori Y, Kikuchi H, Susa K, Chong JX, Bamshad MJ, Tan YQ, Zhang F, Uchida S, Sohara E. CFAP47 is Implicated in X-Linked Polycystic Kidney Disease. Kidney Int Rep 2024; 9:3580-3591. [PMID: 39698362 PMCID: PMC11652189 DOI: 10.1016/j.ekir.2024.09.013] [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: 07/05/2024] [Revised: 09/06/2024] [Accepted: 09/16/2024] [Indexed: 12/20/2024] Open
Abstract
Introduction Autosomal dominant polycystic kidney disease (ADPKD) is a well-described condition in which approximately 80% of all cases have a genetic explanation; and among sporadic cases without a family history, the genetic bases remain unclear in approximately 30% of cases. This study aimed to identify genes associated with polycystic kidney disease (PKD) in patients with sporadic cystic kidney disease in which a clear genetic change was not identified in established genes. Methods A next-generation sequencing panel analyzed known genes related to kidney cysts in 118 sporadic cases, followed by whole-genome sequencing (WGS) on 47 unrelated individuals without identified candidate variants. Immunohistology examination was then conducted on both human kidney tissue and kidneys from CFAP47-/Y mice. Results Three male patients were found to have rare missense variants in the X-linked gene cilia and flagella-associated protein 47 (CFAP47), none of whom had a family history of the condition. CFAP47 was expressed in primary cilia of human kidney tubules, and knockout (KO) mice exhibited vacuolation of tubular cells and tubular dilation, providing evidence that CFAP47 is a causative gene involved in cyst formation. Conclusion This discovery of CFAP47 as a newly identified gene associated with PKD, displaying X-linked inheritance, emphasizes the need for further cases to understand the role of CFAP47 in PKD.
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Affiliation(s)
- Takayasu Mori
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Takuya Fujimaru
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Chunyu Liu
- Soong Ching Ling Institute of Maternal and Child Health, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- State Key Laboratory of Genetic Engineering, Institute of Medical Genetics and Genomics, Fudan University, Shanghai, China
| | - Karynne Patterson
- Department of Genome Sciences, University of Washington, Seattle, Washington, USA
| | - Kouhei Yamamoto
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Takefumi Suzuki
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Motoko Chiga
- Clinical Laboratory, Institute of Science Tokyo Hospital, Tokyo, Japan
| | - Akinari Sekine
- Department of Nephrology and Rheumatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Yoshifumi Ubara
- Department of Nephrology and Rheumatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Danny E. Miller
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA
- Brotman-Baty Institute for Precision Medicine, Seattle, Washington, USA
| | - Miranda P.G. Zalusky
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA
| | - Shintaro Mandai
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Fumiaki Ando
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Yutaro Mori
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Hiroaki Kikuchi
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Koichiro Susa
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Jessica X. Chong
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA
- Brotman-Baty Institute for Precision Medicine, Seattle, Washington, USA
| | - Michael J. Bamshad
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA
- Brotman-Baty Institute for Precision Medicine, Seattle, Washington, USA
| | - Yue-Qiu Tan
- Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, China
- Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
| | - Feng Zhang
- Soong Ching Ling Institute of Maternal and Child Health, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- State Key Laboratory of Genetic Engineering, Institute of Medical Genetics and Genomics, Fudan University, Shanghai, China
| | - Shinichi Uchida
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Eisei Sohara
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
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Thompson WS, Babayev SN, McGowan ML, Kattah AG, Wick MJ, Bendel-Stenzel EM, Chebib FT, Harris PC, Dahl NK, Torres VE, Hanna C. State of the Science and Ethical Considerations for Preimplantation Genetic Testing for Monogenic Cystic Kidney Diseases and Ciliopathies. J Am Soc Nephrol 2024; 35:235-248. [PMID: 37882743 PMCID: PMC10843344 DOI: 10.1681/asn.0000000000000253] [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: 08/19/2023] [Accepted: 10/03/2023] [Indexed: 10/27/2023] Open
Abstract
There is a broad phenotypic spectrum of monogenic polycystic kidney diseases (PKDs). These disorders often involve cilia-related genes and lead to the development of fluid-filled cysts and eventual kidney function decline and failure. Preimplantation genetic testing for monogenic (PGT-M) disorders has moved into the clinical realm. It allows prospective parents to avoid passing on heritable diseases to their children, including monogenic PKD. The PGT-M process involves embryo generation through in vitro fertilization, with subsequent testing of embryos and selective transfer of those that do not harbor the specific disease-causing variant(s). There is a growing body of literature supporting the success of PGT-M for autosomal-dominant and autosomal-recessive PKD, although with important technical limitations in some cases. This technology can be applied to many other types of monogenic PKD and ciliopathies despite the lack of existing reports in the literature. PGT-M for monogenic PKD, like other forms of assisted reproductive technology, raises important ethical questions. When considering PGT-M for kidney diseases, as well as the potential to avoid disease in future generations, there are regulatory and ethical considerations. These include limited government regulation and unstandardized consent processes, potential technical errors, high cost and equity concerns, risks associated with pregnancy for mothers with kidney disease, and the impact on all involved in the process, including the children who were made possible with this technology.
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Affiliation(s)
- Whitney S. Thompson
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
- Biomedical Ethics Research Program, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
- Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota
- Division of Neonatal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Samir N. Babayev
- Division of Reproductive Endocrinology and Infertility, Mayo Clinic, Rochester, Minnesota
- Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota
| | - Michelle L. McGowan
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
- Biomedical Ethics Research Program, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Andrea G. Kattah
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Myra J. Wick
- Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota
- Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota
| | | | - Fouad T. Chebib
- Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, Florida
| | - Peter C. Harris
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Neera K. Dahl
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Vicente E. Torres
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Christian Hanna
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
- Division of Pediatric Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
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Sekine A, Hidaka S, Moriyama T, Shikida Y, Shimazu K, Ishikawa E, Uchiyama K, Kataoka H, Kawano H, Kurashige M, Sato M, Suwabe T, Nakatani S, Otsuka T, Kai H, Katayama K, Makabe S, Manabe S, Shimabukuro W, Nakanishi K, Nishio S, Hattanda F, Hanaoka K, Miura K, Hayashi H, Hoshino J, Tsuchiya K, Mochizuki T, Horie S, Narita I, Muto S. Cystic Kidney Diseases That Require a Differential Diagnosis from Autosomal Dominant Polycystic Kidney Disease (ADPKD). J Clin Med 2022; 11:6528. [PMID: 36362756 PMCID: PMC9657046 DOI: 10.3390/jcm11216528] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/14/2022] [Accepted: 11/01/2022] [Indexed: 09/05/2023] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cystic kidney disease, with patients often having a positive family history that is characterized by a similar phenotype. However, in atypical cases, particularly those in which family history is unclear, a differential diagnosis between ADPKD and other cystic kidney diseases is important. When diagnosing ADPKD, cystic kidney diseases that can easily be excluded using clinical information include: multiple simple renal cysts, acquired cystic kidney disease (ACKD), multilocular renal cyst/multilocular cystic nephroma/polycystic nephroma, multicystic kidney/multicystic dysplastic kidney (MCDK), and unilateral renal cystic disease (URCD). However, there are other cystic kidney diseases that usually require genetic testing, or another means of supplementing clinical information to enable a differential diagnosis of ADPKD. These include autosomal recessive polycystic kidney disease (ARPKD), autosomal dominant tubulointerstitial kidney disease (ADTKD), nephronophthisis (NPH), oral-facial-digital (OFD) syndrome type 1, and neoplastic cystic kidney disease, such as tuberous sclerosis (TSC) and Von Hippel-Lindau (VHL) syndrome. To help physicians evaluate cystic kidney diseases, this article provides a review of cystic kidney diseases for which a differential diagnosis is required for ADPKD.
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Affiliation(s)
- Akinari Sekine
- Nephrology Center, Toranomon Hospital, Tokyo 105-8470, Japan
| | - Sumi Hidaka
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan
| | - Tomofumi Moriyama
- Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Fukuoka 830-0011, Japan
| | - Yasuto Shikida
- Department of Nephrology, Saiseikai Nakatsu Hospital, Osaka 530-0012, Japan
| | - Keiji Shimazu
- Department of Nephrology, Saiseikai Nakatsu Hospital, Osaka 530-0012, Japan
| | - Eiji Ishikawa
- Department of Nephrology, Saiseikai Matsusaka General Hospital, Mie 515-8557, Japan
| | - Kiyotaka Uchiyama
- Department of Endocrinology, Metabolism and Nephrology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hiroshi Kataoka
- Department of Nephrology, Tokyo Women’s Medical University, Tokyo 162-8666, Japan
| | - Haruna Kawano
- Department of Urology, Juntendo University Graduate School of Medicine, Tokyo 113-0033, Japan
- Department of Advanced Informatics for Genetic Disease, Juntendo University Graduate School of Medicine, Tokyo 113-0033, Japan
| | - Mahiro Kurashige
- Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Mai Sato
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo 157-8535, Japan
| | - Tatsuya Suwabe
- Nephrology Center, Toranomon Hospital, Tokyo 105-8470, Japan
| | - Shinya Nakatani
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Tadashi Otsuka
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Hirayasu Kai
- Department of Nephrology, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
| | - Kan Katayama
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Mie 514-8507, Japan
| | - Shiho Makabe
- Department of Nephrology, Tokyo Women’s Medical University, Tokyo 162-8666, Japan
| | - Shun Manabe
- Department of Nephrology, Tokyo Women’s Medical University, Tokyo 162-8666, Japan
| | - Wataru Shimabukuro
- Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | - Koichi Nakanishi
- Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | - Saori Nishio
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Fumihiko Hattanda
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Kazushige Hanaoka
- Department of General Internal Medicine, Daisan Hospital, Jikei University, School of Medicine, Tokyo 105-8471, Japan
| | - Kenichiro Miura
- Department of Pediatric Nephrology, Tokyo Women’s Medical University, Tokyo 162-8666, Japan
| | - Hiroki Hayashi
- Department of Nephrology, Fujita Health University, Aichi 470-1192, Japan
| | - Junichi Hoshino
- Department of Nephrology, Tokyo Women’s Medical University, Tokyo 162-8666, Japan
| | - Ken Tsuchiya
- Department of Blood Purification, Tokyo Women’s Medical University, Tokyo 162-8666, Japan
| | | | - Shigeo Horie
- Department of Urology, Juntendo University Graduate School of Medicine, Tokyo 113-0033, Japan
- Department of Advanced Informatics for Genetic Disease, Juntendo University Graduate School of Medicine, Tokyo 113-0033, Japan
| | - Ichiei Narita
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Satoru Muto
- Department of Urology, Juntendo University Graduate School of Medicine, Tokyo 113-0033, Japan
- Department of Urology, Juntendo University Nerima Hospital, Tokyo 177-8521, Japan
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Whole-Exon Sequencing and Correlation Analysis of a 14-Month-Old Girl With Orofaciodigital Syndrome. J Craniofac Surg 2022; 33:e831-e834. [DOI: 10.1097/scs.0000000000008764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 04/04/2022] [Indexed: 11/07/2022] Open
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Expanding the phenotype of males with OFD1 pathogenic variants-a case report and literature review. Eur J Med Genet 2022; 65:104496. [PMID: 35398350 PMCID: PMC10369588 DOI: 10.1016/j.ejmg.2022.104496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 01/31/2022] [Accepted: 03/29/2022] [Indexed: 11/23/2022]
Abstract
Pathogenic variants in the OFD1 gene have been classically associated with the Orofaciodigital syndrome type 1 in females, a condition previously considered to be X-linked dominant with male embryonic lethality. However, an increasing number of males with pathogenic OFD1 variants who survived beyond the neonatal period have now been reported in the literature. Although each new report has added to the ever-broadening spectrum of clinical findings seen in males, many questions about genotype-phenotype correlations and disease mechanism remain. Herein, we describe a 9-year-old male child with a novel hemizygous pathogenic OFD1 variant identified by exome sequencing and a unique combination of findings, not previously reported, including presence of both a hypothalamic hamartoma and the molar tooth sign. His clinical features overlap multiple ciliopathy phenotypes, blurring the boundaries of distinct ciliopathy gene-disease relationships. This case provides further evidence for the consideration of a broad OFD1-relateddisorder spectrum in affected males rather than multiple distinct phenotypes. Additionally, a review of previously published cases of the disorder in males support the inclusion of the OFD1 gene in the differential diagnosis and work up for all individuals who present with primary ciliopathy-type features, regardless of their gender. We also highlight current information about OFD1 variant types and pathogenesis and explore how these could mechanistically drive some of the observed phenotypic differences.
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Ko YW, Ko JY, Ro YS, Kim JE. Oral-Facial-Digital Syndrome Type 1: A Case Report and Review. Ann Dermatol 2022; 34:132-135. [PMID: 35450320 PMCID: PMC8989907 DOI: 10.5021/ad.2022.34.2.132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 06/18/2020] [Accepted: 07/01/2020] [Indexed: 11/18/2022] Open
Abstract
Oral-facial-digital syndrome type 1 (OFD1), first described by Papillon-Léage in 1954, is transmitted as an X-linked dominant condition and is characterized by a combination of malformations in the face, oral cavity, and digits. Malformations of the brain and polycystic kidney disease are also commonly associated with OFD1. An 11-month-old female presented with multiple tiny whitish papules on her face that had been present since birth. The histopathologic examination was consistent with milium. She also had congenital anomalies, including incomplete cleft palate, bifid tongue, short frenulum, anomalous deformities of both toes, and clino-brachy-syndactyly. Based on the characteristic dysmorphic features of her face, mouth, and hands, a clinical diagnosis of OFD1 was made. Herein, we report a rare case of OFD1 featuring congenital milia, which has not been previously reported in the Korean literature.
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Affiliation(s)
- Young Wook Ko
- Department of Dermatology, Hanyang University Medical Center, Seoul, Korea
| | - Joo Yeon Ko
- Department of Dermatology, Hanyang University Medical Center, Seoul, Korea
| | - Young Suck Ro
- Department of Dermatology, Hanyang University Medical Center, Seoul, Korea
| | - Jeong Eun Kim
- Department of Dermatology, Hanyang University Medical Center, Seoul, Korea
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8
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Magistrati E, Maestrini G, Niño CA, Lince-Faria M, Beznoussenko G, Mironov A, Maspero E, Bettencourt-Dias M, Polo S. Myosin VI regulates ciliogenesis by promoting the turnover of the centrosomal/satellite protein OFD1. EMBO Rep 2021; 23:e54160. [PMID: 34957672 PMCID: PMC8892233 DOI: 10.15252/embr.202154160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/01/2021] [Accepted: 12/08/2021] [Indexed: 11/11/2022] Open
Abstract
The actin motor protein myosin VI is a multivalent protein with diverse functions. Here, we identified and characterised a myosin VI ubiquitous interactor, the oral‐facial‐digital syndrome 1 (OFD1) protein, whose mutations cause malformations of the face, oral cavity, digits and polycystic kidney disease. We found that myosin VI regulates the localisation of OFD1 at the centrioles and, as a consequence, the recruitment of the distal appendage protein Cep164. Myosin VI depletion in non‐tumoural cell lines causes an aberrant localisation of OFD1 along the centriolar walls, which is due to a reduction in the OFD1 mobile fraction. Finally, loss of myosin VI triggers a severe defect in ciliogenesis that could be, at least partially, ascribed to an impairment in the autophagic removal of OFD1 from satellites. Altogether, our results highlight an unprecedent layer of regulation of OFD1 and a pivotal role of myosin VI in coordinating the formation of the distal appendages and primary cilium with important implications for the genetic disorders known as ciliopathies.
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Affiliation(s)
- Elisa Magistrati
- IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
| | - Giorgia Maestrini
- IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
| | - Carlos A Niño
- IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
| | | | | | - Alexandre Mironov
- IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
| | - Elena Maspero
- IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
| | | | - Simona Polo
- IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.,Dipartimento di Oncologia ed Emato-oncologia, Università degli Studi di Milano, Milan, Italy
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9
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Tsao AL, Sperati CJ. Cystic Kidneys in a Patient with Craniofacial Abnormalities. KIDNEY360 2020; 1:882-883. [PMID: 35372955 PMCID: PMC8815731 DOI: 10.34067/kid.0001332020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 03/23/2020] [Indexed: 06/14/2023]
Affiliation(s)
- Allison L. Tsao
- Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
| | - C. John Sperati
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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10
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Saralamma VVG, Vetrivel P, Lee HJ, Kim SM, Ha SE, Murugesan R, Kim EH, Heo JD, Kim GS. Comparative proteomic analysis uncovers potential biomarkers involved in the anticancer effect of Scutellarein in human gastric cancer cells. Oncol Rep 2020; 44:939-958. [PMID: 32705238 PMCID: PMC7388386 DOI: 10.3892/or.2020.7677] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 05/28/2020] [Indexed: 02/07/2023] Open
Abstract
Scutellarein (SCU), a flavone that belongs to the flavonoid family and abundantly present in Scutellaria baicalensis a flowering plant in the family Lamiaceae, has been reported to exhibit anticancer effects in several cancer cell lines including gastric cancer (GC). Although our previous study documented the mechanisms of Scutellarein‑induced cytotoxic effects, the literature shows that the proteomic changes that are associated with the cellular response to SCU have been poorly understood. To avoid adverse side‑effects and significant toxicity of chemotherapy in patients who react poorly, biomarkers anticipating therapeutic responses are imperative. In the present study, we utilized a comparative proteomic analysis to identify proteins associated with Scutellarein (SCU)‑induced cell death in GC cells (AGS and SNU484), by integrating two‑dimensional gel electrophoresis (2‑DE), mass spectrometry (MS), and bioinformatics to analyze the proteins. Proteomic analysis between SCU‑treated and DMSO (control) samples successfully identified 41 (AGS) and 31 (SNU484) proteins by MALDI‑TOF/MS analysis and protein database search. Comparative proteomics analysis between AGS and SNU484 cells treated with SCU revealed a total of 7 protein identities commonly expressed and western blot analysis validated a subset of identified critical proteins, which were consistent with those of the 2‑DE outcome. Molecular docking studies also confirmed the binding affinity of SCU towards these critical proteins. Phosphatidylinositol 4,5‑bisphosphate 3‑kinase catalytic subunit β isoform (PIK3CB) protein expression was accompanied by a distinct group of cellular functions, including cell growth, and proliferation. Cancerous inhibitor of protein phosphatase 2A (CIP2A), is one of the oncogenic molecules that have been shown to promote tumor growth and resistance to apoptosis and senescence‑inducing therapies. In the present study, both PIK3CB and CIP2A proteins were downregulated in SCU‑treated cells, which boosts our previous results of SCU to induce apoptosis and inhibits GC cell growth by regulating these critical proteins. The comparative proteomic analysis has yielded candidate biomarkers of response to SCU treatment in GC cell models and further validation of these biomarkers will help the future clinical development of SCU as a novel therapeutic drug.
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Affiliation(s)
- Venu Venkatarame Gowda Saralamma
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju, Gyeongnam 52828, Republic of Korea
| | - Preethi Vetrivel
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju, Gyeongnam 52828, Republic of Korea
| | - Ho Jeong Lee
- Gyeongnam Department of Environment Toxicology and Chemistry, Biological Resources Research Group, Korea Institute of Toxicology, Jinju, Gyeongnam 52834, Republic of Korea
| | - Seong Min Kim
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju, Gyeongnam 52828, Republic of Korea
| | - Sang Eun Ha
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju, Gyeongnam 52828, Republic of Korea
| | - Rajeswari Murugesan
- Department of Biochemistry, Biotechnology and Bioinformatics, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, Tamil Nadu 641043, India
| | - Eun Hee Kim
- Department of Nursing Science, International University of Korea, Jinju, Gyeongnam 52833, Republic of Korea
| | - Jeong Doo Heo
- Gyeongnam Department of Environment Toxicology and Chemistry, Biological Resources Research Group, Korea Institute of Toxicology, Jinju, Gyeongnam 52834, Republic of Korea
| | - Gon Sup Kim
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju, Gyeongnam 52828, Republic of Korea
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11
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Wiesener A, Knaup KX, Büttner-Herold M, Dieterle A, Stoeckert J, Riedl B, Morath C, Wald A, Vondran F, Braun F, Schödel J, Schueler M, Schiffer M, Amann K, Reis A, Kraus C, Wiesener MS. Molecular diagnosis of kidney transplant failure based on urine. Am J Transplant 2020; 20:1410-1416. [PMID: 31814324 DOI: 10.1111/ajt.15738] [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: 07/26/2019] [Revised: 11/06/2019] [Accepted: 11/23/2019] [Indexed: 01/25/2023]
Abstract
In light of the organ shortage, there is a great responsibility to assess postmortal organs for which procurement has been consented and to increase the life span of transplanted organs. The former responsibility has moved many centers to accept extended criteria organs. The latter responsibility requires an exact diagnosis and, if possible, omission of the harmful influence on the transplant. We report the course of a kidney transplant that showed a steady decline of function over a decade, displaying numerous cysts of different sizes. Clinical workup excluded the most frequent causes of chronic transplant failure. The filed allocation documents mentioned the donor's disease of oral-facial-digital syndrome, a rare ciliopathy, which can also affect the kidney. Molecular diagnosis was performed by culturing donor tubular cells from the recipient´s urine more than 10 years after transplantation. Next-generation panel sequencing with DNA from tubular urinary cells revealed a novel truncating mutation in OFD1, which sufficiently explains the features of the kidney transplants, also found in the second kidney allograft. Despite this severe donor disease, lifesaving transplantation with good long-term outcome was enabled for 5 recipients.
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Affiliation(s)
- Antje Wiesener
- Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Karl X Knaup
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Maike Büttner-Herold
- Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Anne Dieterle
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Johanna Stoeckert
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Bernhard Riedl
- KfH-Nierenzentrum, Kuratorium für Dialyse und Nierentransplantation e.V., Bayreuth, Germany
| | - Christian Morath
- Nierenzentrum Heidelberg, University Hospital Heidelberg, Heidelberg University, Germany
| | - Alexandra Wald
- Department of Pneumology, University Hospital Leipzig, Leipzig, Germany
| | - Florian Vondran
- Department of General, Visceral- and Transplant Surgery, Medical School Hannover, Hannover, Germany
| | - Felix Braun
- Department of General Surgery, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Johannes Schödel
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Markus Schueler
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Mario Schiffer
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Kerstin Amann
- Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - André Reis
- Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Cornelia Kraus
- Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Michael S Wiesener
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
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12
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Morisada N, Hamada R, Miura K, Ye MJ, Nozu K, Hattori M, Iijima K. Bardet-Biedl syndrome in two unrelated patients with identical compound heterozygous SCLT1 mutations. CEN Case Rep 2020; 9:260-265. [PMID: 32253632 DOI: 10.1007/s13730-020-00472-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 03/29/2020] [Indexed: 12/23/2022] Open
Abstract
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by retinitis pigmentosa (RP), truncal obesity, cognitive impairment, hypogonadism in men, polydactyly, and renal abnormalities with severe renal dysfunction. Twenty-two causative genes have already been reported for this disorder. In this study, we identified two unrelated Japanese patients with clinical diagnoses of BBS associated with compound heterozygous SCLT1 mutation. Patient 1 was a 10-year-old girl, and patient 2 was a 22-year-old man. Both the patients showed severe renal dysfunction in childhood, RP, mild intellectual disability, short stature, and truncal obesity, without oral aberrations and polydactyly. Patient 2 also had hypogonadism. We identified two missense variants in SCLT1, c.[1218G > A] and [1631A > G], in both the patients by next-generation sequencing. Subsequent cDNA analysis revealed that c.1218G > A affected exon 14 skipping in SCLT1. To date, SCLT1 has been reported as the causative gene of oral-facial-digital syndrome type IX, and Senior-Løken syndrome. The phenotypes of both the present patients were compatible with BBS. These results highlight SCLT1 as an additional candidate for BBS phenotype in an autosomal recessive manner.
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Affiliation(s)
- Naoya Morisada
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan. .,Department of Clinical Genetics, Hyogo Prefectural Kobe Children's Hospital, 1-6-7, Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
| | - Riku Hamada
- Department of Nephrology, Tokyo Metropolitan Children's Medical Center, 2-8-29, Musashidai, Fuchu, Tokyo, 183-8561, Japan
| | - Kenichiro Miura
- Department of Pediatric Nephrology, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Ming Juan Ye
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Motoshi Hattori
- Department of Pediatric Nephrology, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Kazumoto Iijima
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
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13
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Zhang HW, Su BG, Yao Y. OFD1 mutation induced renal failure and polycystic kidney disease in a pair of childhood male twins in China. World J Clin Cases 2020; 8:331-336. [PMID: 32047782 PMCID: PMC7000948 DOI: 10.12998/wjcc.v8.i2.331] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 12/05/2019] [Accepted: 12/22/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Oral-facial-digital syndrome type 1 (OFD1) is a rare ciliopathy mainly with an X-linked dominant pattern of inheritance, which is caused by mutations in the OFD1 gene. The OFD1 protein is located within the centrosomes and basal bodies of the primary cilia. It is reported that approximately 15%–50% cases of OFD1 progress to end-stage renal disease (ESRD) following development of polycystic kidney diseases (PKD). Here we report a pair of childhood male twins who presented only renal failure and PKD caused by an OFD1 mutation in China.
CASE SUMMARY A pair of 14-year male twins were hospitalized with a complaint of abnormal renal function for nine days. They both complained of ankle pain for 3 mo vs 2 wk, respectively. They denied fever, abdominal pain, daytime or nighttime enuresis, urgency, dysuria, or gross hematuria. Laboratory tests at a local hospital showed renal failure (serum creatinine 485 μmol/L vs 442 μmol/L, blood urea nitrogen 14.7 mol/L vs 14.5 mol/L) and anemia (hemoglobin 88 g/L vs 98 g/L). The twins are monozygotic. There was no abnormal birth, past medical, or family history. Clinical data were analyzed and genetic analysis on PKD was carried out in the twins by next-generation sequencing. The results showed that the twins presented low-molecular-weight proteinuria, hyposthenuria, anemia, renal failure, and renal polycystic changes. Genetic tests showed that the twins both carried a hemizygous mutation in exon 19 c.2524G>A (p. G842R) of the OFD1 gene. Their mother heterozygously carried the same mutation as the twins but was without any phenotypes while their father was normal.
CONCLUSION We have reported a pair of childhood male twins with an OFD1 mutation who presented ESRD and PKD but without any other phenotypes of OFD1 in China.
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Affiliation(s)
- Hong-Wen Zhang
- Department of Pediatrics, Peking University First Hospital, Beijing 100034, China
| | - Bai-Ge Su
- Department of Pediatrics, Peking University First Hospital, Beijing 100034, China
| | - Yong Yao
- Department of Pediatrics, Peking University First Hospital, Beijing 100034, China
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14
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Pinna R, Cocco F, Campus G, Conti G, Milia E, Sardella A, Cagetti MG. Genetic and developmental disorders of the oral mucosa: Epidemiology; molecular mechanisms; diagnostic criteria; management. Periodontol 2000 2019; 80:12-27. [PMID: 31090139 DOI: 10.1111/prd.12261] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A large number of disorders may affect the oral cavity, including genetic diseases, infections, cancers, blood diseases, skin diseases, endocrine and metabolic disorders, autoimmune and rheumatologic diseases, local lesions, to name a few. Oral mucosa shows a considerable variation in its normal structure and a wide range of conditions may affect it. Such conditions are often harmless or minor and could be primary or secondary to systemic disease. Several of them are quite rare and, hence, the diagnosis is not easy. Clinically, lesions may appear as ulcers, discoloration of the oral mucosa and alterations in size and configuration of oral anatomy. Genetic disorders have specific manifestations and can be caused by a derangement of one or more components of the tissue. Many of them follow the skin or systemic signs of the underlying genetic disease, but in a few cases oral signs could be the first manifestation of the disorder. Among them genodermatoses are prominent. They are inherited disorders characterized by a multisystem involvement. This review describes chondro-ectodermal dysplasia, dyskeratosis congenita, Ehlers-Danlos syndrome, hereditary benign intraepithelial dyskeratosis, keratosis follicularis, lipoid proteinosis, multiple hamartoma syndrome, pachyonychia congenita, Peutz-Jeghers syndrome, tuberous sclerosis and white sponge nevus. Other genetic disorders not included in the genodermatosis group and reported in the present review are: acanthosis nigricans, angio-osteo-hypertrophic syndrome, encephalotrigeminal angiomatosis, familial adenomatous polyposis, focal dermal hypoplasia, focal palmoplantar and oral mucosa hyperkeratosis syndrome, gingival fibromatosis, Maffucci's syndrome, neurofibromatosis (type 1) and oro-facial-digital syndrome (type 1). Disorders during embryonic development might lead to a wide range of abnormalities in the oral cavity; some of them are quite common but of negligible concern, whereas others are rare but serious, affecting not only the oral mucosa, but also other structures of the oral cavity (ie palate, tongue and gingiva). Fordyce's granules, leukoedema, cysts of the oral mucosa in newborns, retrocuspid papilla, geographic tongue, fissured tongue, median rhomboid glossitis, hairy tongue, lingual varices and lingual thyroid nodule are described. This review may help dentists, dental hygienists, but also general internists and pediatricians to diagnose different disorders of the oral mucosa, to understand the pathogenesis and to schedule a treatment plan.
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Affiliation(s)
- Roberto Pinna
- Department of Surgery, Medicine and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Fabio Cocco
- Department of Surgery, Medicine and Experimental Sciences, University of Sassari, Sassari, Italy.,WHO Collaboration Centre for Epidemiology and Community Dentistry, University of Milan, Milan, Italy
| | - Guglielmo Campus
- Department of Surgery, Medicine and Experimental Sciences, University of Sassari, Sassari, Italy.,WHO Collaboration Centre for Epidemiology and Community Dentistry, University of Milan, Milan, Italy.,Klinik für Zahnerhaltung, Präventiv-und Kinderzahnmedizin Zahnmedizinische Kliniken (ZMK), University of Bern, Switzerland
| | - Giulio Conti
- IRCCS "Ca Granda-Ospedale Maggiore", University of Milan, Milan, Italy
| | - Egle Milia
- Department of Surgery, Medicine and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Andrea Sardella
- IRCCS "Ca Granda-Ospedale Maggiore", University of Milan, Milan, Italy.,Department of Biomedical, Surgical and Dental Science, University of Milan, Milan, Italy
| | - Maria Grazia Cagetti
- WHO Collaboration Centre for Epidemiology and Community Dentistry, University of Milan, Milan, Italy.,Department of Biomedical, Surgical and Dental Science, University of Milan, Milan, Italy
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15
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Kilinc DD, Ozsarp E. Papillon-Léage and psaume syndrome patient with multiple dental and orofacial anomalies. Niger J Clin Pract 2019; 22:872-876. [PMID: 31187776 DOI: 10.4103/njcp.njcp_451_18] [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] [Indexed: 11/04/2022]
Abstract
Papillon-Léage-Psaume Syndrome, also known as oral-facial-digital syndrome (OFDS) type I, describes a group of neurodevelopmental disorders that are characterized by anomalies of the oral cavity, facial features, and the digits. Central nervous system (CNS) anomalies and visceral organ abnormalities such as kidney, pancreas, and ovarian cysts can also be seen in these patients. Among 13 potential types, female-inherited OFDS type I is the most common and it has been reported to be lethal in males. After the identification of the genetic relation of OFDS in 2001, it is now known that, except X-linked OFDS Type I and VIII, generally all types of OFDSs are autosomal recessive. The dentist's knowledge about the syndrome can reduce the development of physical and dental anomalies by facilitating early diagnosis. This article presents a patient with Papillon-Léage-Psaume Syndrome (Oral-Facial-Digital Syndrome Type I).
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Affiliation(s)
- D D Kilinc
- Department of Orthodontics, Faculty of Dentistry, Istanbul Medipol University, Istanbul, Turkey
| | - E Ozsarp
- Department of Orthodontics, Faculty of Dentistry, Istanbul Medipol University, Istanbul, Turkey
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16
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Alby C, Boutaud L, Bonnière M, Collardeau-Frachon S, Guibaud L, Lopez E, Bruel AL, Aral B, Sonigo P, Roth P, Vibert-Guigue C, Castaigne V, Carbonne B, Joyé N, Faivre L, Cordier MP, Bernabe Gelot A, Clementi M, Mammi I, Vekemans M, Razavi F, Gonzales M, Thauvin-Robinet C, Attié-Bitach T. In utero ultrasound diagnosis of corpus callosum agenesis leading to the identification of orofaciodigital type 1 syndrome in female fetuses. Birth Defects Res 2017; 110:382-389. [PMID: 29193896 DOI: 10.1002/bdr2.1154] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 10/09/2017] [Accepted: 10/13/2017] [Indexed: 01/25/2023]
Abstract
BACKGROUND OFD1 syndrome is a rare ciliopathy inherited on a dominant X-linked mode, typically lethal in males in the first or second trimester of pregnancy. It is characterized by oral cavity and digital anomalies possibly associated with cerebral and renal signs. Its prevalence is between 1/250,000 and 1/50,000 births. It is due to heterozygous mutations of OFD1 and mutations are often de novo (75%). Familial forms show highly variable phenotypic expression. OFD1 encodes a protein involved in centriole growth, distal appendix formation, and ciliogenesis. CASES We report the investigation of three female fetuses in which corpus callosum agenesis was detected by ultrasound during the second trimester of pregnancy. In all three fetuses, fetopathological examination allowed the diagnosis of OFD1 syndrome, which was confirmed by molecular analysis. CONCLUSIONS To our knowledge, these are the first case reports of antenatal diagnosis of OFD1 syndrome in the absence of familial history, revealed following detection of agenesis of the corpus callosum. They highlight the impact of fetal examination following termination of pregnancy for brain malformations. They also highlight the contribution of ciliary genes to corpus callosum development.
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Affiliation(s)
- Caroline Alby
- INSERM U1163, Institut Imagine, Université Paris Descartes, Paris, France.,Unité d'Embryofoetopathologie, Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | - Lucile Boutaud
- INSERM U1163, Institut Imagine, Université Paris Descartes, Paris, France.,Unité d'Embryofoetopathologie, Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | - Maryse Bonnière
- Unité d'Embryofoetopathologie, Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | - Sophie Collardeau-Frachon
- Département d'anatomopathologie, Hôpital-Femme-Mère-Enfant, Hospices Civils de Lyon, Lyon, France.,Université Claude Bernard Lyon I, CHU de Lyon, Lyon, France
| | - Laurent Guibaud
- Université Claude Bernard Lyon I, CHU de Lyon, Lyon, France.,Service de radiologie, Hôpital-Femme-Mère-Enfant, Hospices Civils de Lyon, Lyon, France
| | - Estelle Lopez
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Grand-Est, Hôpital d'Enfants, FHU TRANSLAD CHU Dijon Bourgogne, Dijon, France.,UMR 1231, GAD Inserm Université de Bourgogne, Dijon, France
| | - Ange-Line Bruel
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Grand-Est, Hôpital d'Enfants, FHU TRANSLAD CHU Dijon Bourgogne, Dijon, France.,UMR 1231, GAD Inserm Université de Bourgogne, Dijon, France
| | - Bernard Aral
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Grand-Est, Hôpital d'Enfants, FHU TRANSLAD CHU Dijon Bourgogne, Dijon, France.,UMR 1231, GAD Inserm Université de Bourgogne, Dijon, France
| | - Pascale Sonigo
- Service de Radiologie Pédiatrique, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | - Philippe Roth
- Service de Gynécologie Obstétrique, Necker-Enfants Malades, APHP, Paris, France
| | - Claude Vibert-Guigue
- Service de Gynécologie-Obstétrique, Groupe Hospitalier Pitié-Salpêtrière, APHP, Paris, France
| | - Vanina Castaigne
- Unité de Diagnostic Anténatal, Service de Gynécologie Obstétrique, Hôpital Intercommunal de Créteil, Créteil Cedex, France
| | - Bruno Carbonne
- Service Département de Gynécologie-Obstétrique, Hôpital Princesse Grace, Monaco
| | - Nicole Joyé
- Département de Génétique Médicale, Hôpital Armand Trousseau, APHP, UPMC-Sorbonne Universités, Paris, France
| | - Laurence Faivre
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Grand-Est, Hôpital d'Enfants, FHU TRANSLAD CHU Dijon Bourgogne, Dijon, France.,UMR 1231, GAD Inserm Université de Bourgogne, Dijon, France
| | | | | | - Maurizio Clementi
- Sezione di Genetica Clinica Epidemiologica, Dipartimento di Pediatria, Azienda Ospedaliera Universitaria di Padova, Padova, Italia
| | - Isabella Mammi
- Ambulatorio di Genetica Medica, Ospedale Dolo, Dolo, Italia
| | - Michel Vekemans
- INSERM U1163, Institut Imagine, Université Paris Descartes, Paris, France.,Unité d'Embryofoetopathologie, Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | - Féréchté Razavi
- INSERM U1163, Institut Imagine, Université Paris Descartes, Paris, France.,Unité d'Embryofoetopathologie, Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | - Marie Gonzales
- Unité d'Embryofoetopathologie, Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, APHP, Paris, France.,Département de Génétique Médicale, Hôpital Armand Trousseau, APHP, UPMC-Sorbonne Universités, Paris, France
| | - Christel Thauvin-Robinet
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Grand-Est, Hôpital d'Enfants, FHU TRANSLAD CHU Dijon Bourgogne, Dijon, France.,UMR 1231, GAD Inserm Université de Bourgogne, Dijon, France
| | - Tania Attié-Bitach
- INSERM U1163, Institut Imagine, Université Paris Descartes, Paris, France.,Unité d'Embryofoetopathologie, Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, APHP, Paris, France
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17
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An Atypical Presentation of a Male with Oral-Facial-Digital Syndrome Type 1 Related Ciliopathy. Case Rep Nephrol 2016; 2016:3181676. [PMID: 27651963 PMCID: PMC5019883 DOI: 10.1155/2016/3181676] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Revised: 08/09/2016] [Accepted: 08/10/2016] [Indexed: 12/11/2022] Open
Abstract
Background. Oral-facial-digital syndrome type 1 (OFD1) is a rare condition with X-linked dominant inheritance caused by mutations in the Cxorf5 (OFD1) gene. This gene encodes the OFD1 protein located within centrosomes and basal bodies of primary cilia. Approximately 15–50% of patients with OFD1 progress to end-stage kidney disease following development of polycystic changes within the kidneys. This condition almost always causes intrauterine lethality in males. Description of Case Diagnosis and Treatment. A Caucasian male aged 9 years and 9 months presented with increased urinary frequency, increased thirst, and decreased appetite. Physical examination demonstrated short stature, hearing loss, photophobia, murmur, and hypogonadism. He had no other dysmorphic features. Laboratory results revealed anemia, renal insufficiency, and dilute urine with microscopic hematuria but no proteinuria. Ultrasound showed small kidneys with increased echogenicity but no evidence of cystic changes. A Ciliopathy Panel showed a novel and likely pathogenic deletion, approximately 7.9 kb, in the OFD1 gene encompassing exons 16, 17, and 19 (c.1654+833_2599+423del). Brain MRI did not demonstrate typical OFD1 findings. He is currently on chronic hemodialysis awaiting transplant from a living donor. Conclusions. We present a male patient with OFD1 mutation who lacks the classic OFD1 phenotype who presented with end-stage renal disease without evidence of polycystic changes within the kidneys.
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18
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Hunter JM, Kiefer J, Balak CD, Jooma S, Ahearn ME, Hall JG, Baumbach-Reardon L. Review of X-linked syndromes with arthrogryposis or early contractures-aid to diagnosis and pathway identification. Am J Med Genet A 2015; 167A:931-73. [DOI: 10.1002/ajmg.a.36934] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 12/05/2014] [Indexed: 02/03/2023]
Affiliation(s)
- Jesse M. Hunter
- Integrated Functional Cancer Genomics; Translational Genomics Research Institute; Phoenix Arizona
| | - Jeff Kiefer
- Knowledge Mining; Translational Genomics Research Institute; Phoenix Arizona
| | - Christopher D. Balak
- Integrated Functional Cancer Genomics; Translational Genomics Research Institute; Phoenix Arizona
| | - Sonya Jooma
- Integrated Functional Cancer Genomics; Translational Genomics Research Institute; Phoenix Arizona
| | - Mary Ellen Ahearn
- Integrated Functional Cancer Genomics; Translational Genomics Research Institute; Phoenix Arizona
| | - Judith G. Hall
- Departments of Medical Genetics and Pediatrics; University of British Columbia and BC Children's Hospital Vancouver; British Columbia Canada
| | - Lisa Baumbach-Reardon
- Integrated Functional Cancer Genomics; Translational Genomics Research Institute; Phoenix Arizona
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19
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Dhull KS, Acharya S, Mohanty M, Dhull RS, Panda S. Oro-facial-digital syndrome type 1: a case report. J Indian Soc Pedod Prev Dent 2014; 32:152-155. [PMID: 24739916 DOI: 10.4103/0970-4388.130980] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Oro-Facial Digital Syndrome (OFDS) is a generic term for group of apparently distinctive genetic diseases that affect the development of the oral cavity, facial features, and digits. One of these is OFDS type I (OFDS-I) which has rarely been reported in Asian countries. This is the case report of a 13 year old patient with OFDS type I who reported to the Department of Pedodontics and Preventive Dentistry, with the complaint of discolored upper front teeth.
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Affiliation(s)
- Kanika Singh Dhull
- Department of Pedodontics and Preventive Dentistry, Kalinga Institute of Dental Sciences, KIIT University, India,
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20
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Tagliani MM, Gomide MR, Carrara CFC. Oral-facial-digital syndrome type 1: oral features in 12 patients submitted to clinical and radiographic examination. Cleft Palate Craniofac J 2014; 47:162-6. [PMID: 20210637 DOI: 10.1597/08-200_1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE To evaluate the oral features in individuals with oral-facial-digital syndrome type 1 (OFD 1), previously diagnosed by the Genetic Sector of the Hospital of Rehabilitation of Craniofacial Anomalies of the University of São Paulo (HRAC-USP). DESIGN Twelve patients with OFD 1 were examined clinically and radiographically; their medical files were also evaluated. RESULTS Associated oral malformations were observed in all patients (100%). The most frequent findings were tongue hamartomas, multiple buccal frena, asymmetric lips, asymmetric tongue, and bilateral maxillary gingival swelling. Interestingly, atrophy of the maxillary midline frenum was also observed in all the individuals examined. CONCLUSIONS Several extra and intraoral alterations were observed in patients with OFD 1. The authors suggest the inclusion of atrophy of the maxillary midline frenum as a commonly found characteristic of OFD 1.
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From bone abnormalities to mineral metabolism dysregulation in autosomal dominant polycystic kidney disease. Pediatr Nephrol 2013; 28:2089-96. [PMID: 23340856 DOI: 10.1007/s00467-012-2384-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Revised: 11/27/2012] [Accepted: 11/28/2012] [Indexed: 01/02/2023]
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of kidney failure. It is a systemic disorder, not only affecting the kidneys, but also associated with cyst formation in other organs such as the liver, spleen, pancreas, and seminal vesicles. Other extra-renal symptoms may consist of intracranial arterial aneurysms, cardiac valvular defects, abdominal and inguinal hernias and colonic diverticulosis. Very little is known regarding bone involvement in ADPKD; however, recent evidence has revealed the potential role of fibroblast growth factor 23 (FGF23). FGF23 is an endocrine fibroblast growth factor acting in the kidney as a phosphaturic hormone and a suppressor of active vitamin D with key effects on the bone/kidney/parathyroid axis, and has been shown to increase in patients with ADPKD, even with normal renal function. The aim of this review is to provide an overview of bone and mineral abnormalities found in experimental models and in patients with ADPKD, and to discuss the possible role of FGF23 in this disease.
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22
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Tang Z, Lin MG, Stowe TR, Chen S, Zhu M, Stearns T, Franco B, Zhong Q. Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites. Nature 2013; 502:254-7. [PMID: 24089205 PMCID: PMC4075283 DOI: 10.1038/nature12606] [Citation(s) in RCA: 325] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Accepted: 08/29/2013] [Indexed: 12/29/2022]
Abstract
The primary cilium is a microtubule-based organelle that functions in sensory and signalling pathways. Defects in ciliogenesis can lead to a group of genetic syndromes known as ciliopathies. However, the regulatory mechanisms of primary ciliogenesis in normal and cancer cells are incompletely understood. Here we demonstrate that autophagic degradation of a ciliopathy protein, OFD1 (oral-facial-digital syndrome 1), at centriolar satellites promotes primary cilium biogenesis. Autophagy is a catabolic pathway in which cytosol, damaged organelles and protein aggregates are engulfed in autophagosomes and delivered to lysosomes for destruction. We show that the population of OFD1 at the centriolar satellites is rapidly degraded by autophagy upon serum starvation. In autophagy-deficient Atg5 or Atg3 null mouse embryonic fibroblasts, OFD1 accumulates at centriolar satellites, leading to fewer and shorter primary cilia and a defective recruitment of BBS4 (Bardet-Biedl syndrome 4) to cilia. These defects are fully rescued by OFD1 partial knockdown that reduces the population of OFD1 at centriolar satellites. More strikingly, OFD1 depletion at centriolar satellites promotes cilia formation in both cycling cells and transformed breast cancer MCF7 cells that normally do not form cilia. This work reveals that removal of OFD1 by autophagy at centriolar satellites represents a general mechanism to promote ciliogenesis in mammalian cells. These findings define a newly recognized role of autophagy in organelle biogenesis.
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Affiliation(s)
- Zaiming Tang
- Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
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González MG, Castro MP, Nieto DV, Bouzán JC. Oral-facial-digital syndrome type I: surgical approach and a case report. J Plast Reconstr Aesthet Surg 2013; 67:396-8. [PMID: 23886557 DOI: 10.1016/j.bjps.2013.06.044] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Accepted: 06/18/2013] [Indexed: 11/29/2022]
Abstract
PURPOSE Oral-facial-digital (OFD) syndromes constitute a heterogeneous group of embrionary development disorders. There are at least 11 different forms, with a broad spectrum of clinical features, causing an important problem with the diagnosis. There are only a few reports in the recent literature, and there is no surgical technique described for its correction. MATERIALS AND METHODS We present a newborn female referred to the Cleft Lip and Palate Division of our hospital with facial dysmorphology; her mother was affected by an incomplete form of this syndrome. Genetic investigation showed a mutation not reported before in the literature. We present the clinical features and a new surgical approach for its correction. RESULTS OFD syndrome type I (OFD I) is characterised by several clinical features, including incomplete central upper lip cleft, bifid tongue, intraoral hamartomas, upper lip frenula and soft palate cleft. With this technique, we get a good aesthetic result. CONCLUSION OFD I is extremely infrequent and it is important to differentiate it from other forms of OFD. We want to emphasise the importance of performing a correct differential diagnosis in patients affected by palate cleft who have intraoral masses or feeding problems, to rule out incomplete forms of this syndrome. Surgical correction of the malformations associated with this syndrome is a challenge for the paediatric surgeon, because none of the previously reported techniques approach the reparation of this central labial defect.
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Affiliation(s)
- M García González
- Hospital Materno Infantil Teresa Herrera A Coruña, Complejo Hospitalario Universitario de A Coruña, Coruña, Spain.
| | - M Pombo Castro
- Hospital Materno Infantil Teresa Herrera A Coruña, Complejo Hospitalario Universitario de A Coruña, Coruña, Spain
| | - D Vela Nieto
- Hospital Materno Infantil Teresa Herrera A Coruña, Complejo Hospitalario Universitario de A Coruña, Coruña, Spain
| | - J Caramés Bouzán
- Hospital Materno Infantil Teresa Herrera A Coruña, Complejo Hospitalario Universitario de A Coruña, Coruña, Spain
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Barboza-Cerda MC, Campos-Acevedo LD, Rangel R, Martínez-de-Villarreal LE, Déctor MA. A novel phenotype characterized by digital abnormalities, intellectual disability, and short stature in a Mexican family maps to Xp11.4-p11.21. Am J Med Genet A 2013; 161A:237-43. [DOI: 10.1002/ajmg.a.35743] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Accepted: 10/08/2012] [Indexed: 11/09/2022]
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Bisschoff IJ, Zeschnigk C, Horn D, Wellek B, Rieß A, Wessels M, Willems P, Jensen P, Busche A, Bekkebraten J, Chopra M, Hove HD, Evers C, Heimdal K, Kaiser AS, Kunstmann E, Robinson KL, Linné M, Martin P, McGrath J, Pradel W, Prescott KE, Roesler B, Rudolf G, Siebers-Renelt U, Tyshchenko N, Wieczorek D, Wolff G, Dobyns WB, Morris-Rosendahl DJ. Novel mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciodigital syndrome: a study of the extensive clinical variability. Hum Mutat 2012; 34:237-47. [PMID: 23033313 DOI: 10.1002/humu.22224] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2012] [Accepted: 09/06/2012] [Indexed: 01/08/2023]
Abstract
OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X-inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability.
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Affiliation(s)
- Izak J Bisschoff
- Institute of Human Genetics, University Clinic Freiburg, Freiburg, Germany
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Abstract
The oral-facial-digital (OFD) syndrome is a heterogeneous group of abnormalities that share anomalies of the oral cavity, face and digits of hands and feet. On the basis of other anomalies of brain, kidneys, limbs, eyes and other organs, at least 13 subgroups have been described. We here describe four unrelated patients with this syndrome, who have the typical facial, oral and digital anomalies and also anomalies of other organs and systems. Facial features, digital malformations, as well as the existence of additional malformations all of which can be classified into different subgroups. The report points out the difficulty in delineation of the subtypes of OFD syndrome because of the overlapping features between OFD subgroups.
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The promise of human induced pluripotent stem cells in dental research. Stem Cells Int 2012; 2012:423868. [PMID: 22654919 PMCID: PMC3357626 DOI: 10.1155/2012/423868] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Revised: 02/20/2012] [Accepted: 02/22/2012] [Indexed: 02/07/2023] Open
Abstract
Induced pluripotent stem cell-based therapy for treating genetic disorders has become an interesting field of research in recent years. However, there is a paucity of information regarding the applicability of induced pluripotent stem cells in dental research. Recent advances in the use of induced pluripotent stem cells have the potential for developing disease-specific iPSC lines in vitro from patients. Indeed, this has provided a perfect cell source for disease modeling and a better understanding of genetic aberrations, pathogenicity, and drug screening. In this paper, we will summarize the recent progress of the disease-specific iPSC development for various human diseases and try to evaluate the possibility of application of iPS technology in dentistry, including its capacity for reprogramming some genetic orodental diseases. In addition to the easy availability and suitability of dental stem cells, the approach of generating patient-specific pluripotent stem cells will undoubtedly benefit patients suffering from orodental disorders.
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Oztürk F, Doruk C. Orthodontic treatment of a patient with oral-facial-digital syndrome. Am J Orthod Dentofacial Orthop 2012; 141:S110-8. [PMID: 22449591 DOI: 10.1016/j.ajodo.2010.09.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Revised: 09/01/2010] [Accepted: 09/01/2010] [Indexed: 11/16/2022]
Abstract
Oral-facial-digital syndrome is characterized by heterogeneous clinical features involving malformations of the face, oral cavity, and digits. The syndrome has been reported only in women, suggesting that it is lethal in males. Affected females have malformations of the oral cavity (cleft palate, lip and tongue, abnormal dentition, and hamartomas), face (hypertelorism and milia), and digits (syndactyly, brachydactyly, and polydactyly). In this article, we report the orthodontic treatment of a 21-year-old woman with oral-facial-digital syndrome.
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Affiliation(s)
- Firat Oztürk
- Department of Orthodontics, Faculty of Dentistry, İnönü University, Malatya, Turkey.
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Chang TC, Klabnik JL, Liu WS. Regional selection acting on the OFD1 gene family. PLoS One 2011; 6:e26195. [PMID: 22022562 PMCID: PMC3193505 DOI: 10.1371/journal.pone.0026195] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Accepted: 09/22/2011] [Indexed: 02/01/2023] Open
Abstract
The OFD1 (oral-facial-digital, type 1) gene is implicated in several developmental disorders in humans. The X-linked OFD1 (OFD1X) is conserved in Eutheria. Knowledge about the Y-linked paralog (OFD1Y) is limited. In this study, we identified an OFD1Y on the bovine Y chromosome, which is expressed differentially from the bovine OFD1X. Phylogenetic analysis indicated that: a) the eutherian OFD1X and OFD1Y were derived from the pair of ancestral autosomes during sex chromosome evolution; b) the autosomal OFD1 pseudogenes, present in Catarrhini and Murinae, were derived from retropositions of OFD1X after the divergence of primates and rodents; and c) the presence of OFD1Y in the ampliconic region of the primate Y chromosome is an indication that the expansion of the ampliconic region may initiate from the X-degenerated sequence. In addition, we found that different regions of OFD1/OFD1X/OFD1Y are under differential selection pressures. The C-terminal half of OFD1 is under relaxed selection with an elevated Ka/Ks ratio and clustered positively selected sites, whereas the N-terminal half is under stronger constraints. This study provides some insights into why the OFD1X gene causes OFD1 (male-lethal X-linked dominant) and SGBS2 & JSRDs (X-linked recessive) syndromes in humans, and reveals the origin and evolution of the OFD1 family, which will facilitate further clinical investigation of the OFD1-related syndromes.
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Affiliation(s)
- Ti-Cheng Chang
- Department of Dairy and Animal Science, The Center for Reproductive Biology and Health, College of Agricultural Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America
- The Integrative Biosciences Program, Bioinformatics and Genomics Option, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Jessica L. Klabnik
- Veterinary and Biomedical Department, College of Agricultural Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Wan-Sheng Liu
- Department of Dairy and Animal Science, The Center for Reproductive Biology and Health, College of Agricultural Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America
- The Integrative Biosciences Program, Bioinformatics and Genomics Option, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America
- * E-mail:
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Lopes CAM, Prosser SL, Romio L, Hirst RA, O'Callaghan C, Woolf AS, Fry AM. Centriolar satellites are assembly points for proteins implicated in human ciliopathies, including oral-facial-digital syndrome 1. J Cell Sci 2011; 124:600-12. [PMID: 21266464 PMCID: PMC3031371 DOI: 10.1242/jcs.077156] [Citation(s) in RCA: 134] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2010] [Indexed: 11/20/2022] Open
Abstract
Ciliopathies are caused by mutations in genes encoding proteins required for cilia organization or function. We show through colocalization with PCM-1, that OFD1 (the product of the gene mutated in oral-facial-digital syndrome 1) as well as BBS4 and CEP290 (proteins encoded by other ciliopathy genes) are primarily components of centriolar satellites, the particles surrounding centrosomes and basal bodies. RNA interference experiments reveal that satellite integrity is mutually dependent upon each of these proteins. Upon satellite dispersal, through mitosis or forced microtubule depolymerization, OFD1 and CEP290 remain centrosomal, whereas BBS4 and PCM-1 do not. OFD1 interacts via its fifth coiled-coil motif with the N-terminal coiled-coil domain of PCM-1, which itself interacts via its C-terminal non-coiled-coil region with BBS4. OFD1 localization to satellites requires its N-terminal region, encompassing the LisH motif, whereas expression of OFD1 C-terminal constructs causes PCM-1 and CEP290 mislocalization. Moreover, in embryonic zebrafish, OFD1 and BBS4 functionally synergize, determining morphogenesis. Our observation that satellites are assembly points for several mutually dependent ciliopathy proteins provides a further possible explanation as to why the clinical spectrum of OFD1, Bardet-Biedl and Joubert syndromes overlap. Furthermore, definition of how OFD1 and PCM-1 interact helps explain why different OFD1 mutations lead to clinically variable phenotypes.
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Affiliation(s)
- Carla A. M. Lopes
- Department of Biochemistry, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK
| | - Suzanna L. Prosser
- Department of Biochemistry, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK
| | - Leila Romio
- Nephro-Urology Unit, University College London Institute of Child Health, London WC1N 1EH, UK
| | - Robert A. Hirst
- Department of Infection, Immunity and Inflammation, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester LE2 7LX, UK
| | - Chris O'Callaghan
- Department of Infection, Immunity and Inflammation, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester LE2 7LX, UK
| | - Adrian S. Woolf
- Developmental Biomedicine Research Group, University of Manchester and Royal Manchester Children's Hospital, Manchester M13 9PT, UK
| | - Andrew M. Fry
- Department of Biochemistry, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK
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Halleux D, Dahan K, Thauvin-Robinet C, Aral B, Pouteil-Noble C, Devuyst O, Pirson Y. Outcome of kidney transplantation in type I oral-facial-digital syndrome. Transpl Int 2011; 24:e48-50. [PMID: 21210864 DOI: 10.1111/j.1432-2277.2010.01208.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Chetty-John S, Piwnica-Worms K, Bryant J, Bernardini I, Fischer RE, Heller T, Gahl WA, Gunay-Aygun M. Fibrocystic disease of liver and pancreas; under-recognized features of the X-linked ciliopathy oral-facial-digital syndrome type 1 (OFD I). Am J Med Genet A 2010; 152A:2640-5. [PMID: 20818665 DOI: 10.1002/ajmg.a.33666] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OFD I is an X-linked dominant male-lethal ciliopathy characterized by prominent external features including oral clefts, hamartomas or cysts of the tongue, and digital anomalies. Although these external features are easy to recognize and often lead to diagnosis in early childhood, visceral findings in OFD I, especially the fibrocystic liver and pancreas disease, are under-recognized. In addition, while the occurrence of polycystic kidney disease (PKD) in OFD I is well known, few patients are evaluated and monitored for this complication. We report on two adult females diagnosed with OFD I in infancy, but not evaluated for visceral involvement. In adulthood, they were incidentally found to have severe hypertension and chronic renal insufficiency due to undiagnosed PKD. A pancreatic cystic lesion, also discovered incidentally, was thought to be malignant and led to consideration of major surgery. We present NIH evaluations, including documentation of OFD I mutations, extreme beading of the intrahepatic bile ducts, pancreatic cysts, and tabulate features of reported OFD I cases having hepatic, pancreatic, and renal cystic disease. Liver and pancreas are not routinely evaluated in OFD I patients. Increased awareness and lifelong monitoring of visceral complications, particularly involving the liver, pancreas, and kidney, are essential for timely and accurate treatment.
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Tagliani MM, Gomide MR, Carrara CFC. Oral-facial-digital syndrome type 1: oral features in 12 patients submitted to clinical and radiographic examination. Cleft Palate Craniofac J 2010. [PMID: 20210637 DOI: 10.1597/08-200.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE To evaluate the oral features in individuals with oral-facial-digital syndrome type 1 (OFD 1), previously diagnosed by the Genetic Sector of the Hospital of Rehabilitation of Craniofacial Anomalies of the University of São Paulo (HRAC-USP). DESIGN Twelve patients with OFD 1 were examined clinically and radiographically; their medical files were also evaluated. RESULTS Associated oral malformations were observed in all patients (100%). The most frequent findings were tongue hamartomas, multiple buccal frena, asymmetric lips, asymmetric tongue, and bilateral maxillary gingival swelling. Interestingly, atrophy of the maxillary midline frenum was also observed in all the individuals examined. CONCLUSIONS Several extra and intraoral alterations were observed in patients with OFD 1. The authors suggest the inclusion of atrophy of the maxillary midline frenum as a commonly found characteristic of OFD 1.
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Prattichizzo C, Macca M, Novelli V, Giorgio G, Barra A, Franco B. Mutational spectrum of the oral-facial-digital type I syndrome: a study on a large collection of patients. Hum Mutat 2008; 29:1237-46. [PMID: 18546297 DOI: 10.1002/humu.20792] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Oral-facial-digital type I (OFDI) syndrome is a male-lethal X-linked dominant developmental disorder belonging to the heterogeneous group of oral-facial-digital syndromes (OFDS). OFDI is characterized by malformations of the face, oral cavity, and digits. Central nervous system (CNS) abnormalities and cystic kidney disease can also be part of this condition. This rare genetic disorder is due to mutations in the OFD1 gene that encodes a centrosome/basal body protein necessary for primary cilium assembly and for left-right axis determination, thus ascribing OFDI to the growing number of disorders associated to ciliary dysfunction. We now report a mutation analysis study in a cohort of 100 unrelated affected individuals collected worldwide. Putative disease-causing mutations were identified in 81 patients (81%). We describe 67 different mutations, 64 of which represent novel mutations, including 36 frameshift, nine missense, 11 splice-site, and 11 nonsense mutations. Most of them concentrate in exons 3, 8, 9, 12, 13, and 16, suggesting that these exons may represent mutational hotspots. Phenotypic characterization of the patients provided a better definition of the clinical features of OFDI syndrome. Our results indicate that renal cystic disease is present in 60% of cases >18 years of age. Genotype-phenotype correlation did not reveal significant associations apart for the high-arched/cleft palate most frequently associated to missense and splice-site mutations. Our results contribute to further expand our knowledge on the molecular basis of OFDI syndrome.
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35
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Berk DR, Bayliss SJ. Milia: A review and classification. J Am Acad Dermatol 2008; 59:1050-63. [DOI: 10.1016/j.jaad.2008.07.034] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2008] [Revised: 07/22/2008] [Accepted: 07/26/2008] [Indexed: 01/01/2023]
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Ferrante MI, Romio L, Castro S, Collins JE, Goulding DA, Stemple DL, Woolf AS, Wilson SW. Convergent extension movements and ciliary function are mediated by ofd1, a zebrafish orthologue of the human oral-facial-digital type 1 syndrome gene. Hum Mol Genet 2008; 18:289-303. [PMID: 18971206 PMCID: PMC2638777 DOI: 10.1093/hmg/ddn356] [Citation(s) in RCA: 106] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
In humans, OFD1 is mutated in oral-facial-digital type I syndrome leading to prenatal death in hemizygous males and dysmorphic faces and brain malformations, with polycystic kidneys presenting later in life in heterozygous females. To elucidate the function of Ofd1, we have studied its function during zebrafish embryonic development. In wild-type embryos, ofd1 mRNA is widely expressed and Ofd1-green fluorescent protein (GFP) fusion localizes to the centrosome/basal body. Disrupting Ofd1 using antisense morpholinos (MOs) led to bent body axes, hydrocephalus and oedema. Laterality was randomized in the brain, heart and viscera, likely a consequence of shorter cilia with disrupted axonemes and perturbed intravesicular fluid flow in Kupffer's vesicle. Embryos injected with ofd1 MOs also displayed convergent extension (CE) defects, which were enhanced by loss of Slb/Wnt11 or Tri/Vangl2, two proteins functioning in a non-canonical Wnt/Planar Cell Polarity (PCP) pathway. Pronephric glomerular midline fusion was compromised in vangl2 and ofd1 loss of function embryos and we suggest this anomaly may be a novel CE defect. Thus, Ofd1 is required for ciliary motility and function in zebrafish, supporting data showing that Ofd1 is essential for primary cilia function in mice. In addition, our data show that Ofd1 is important for CE during gastrulation, consistent with data linking primary cilia and non-canonical Wnt/PCP signalling.
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Affiliation(s)
- Maria I Ferrante
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK
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37
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Ciliary syndromes and treatment. Pathol Res Pract 2008; 204:77-88. [PMID: 18312782 DOI: 10.1016/j.prp.2007.10.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2006] [Revised: 10/26/2007] [Accepted: 10/30/2007] [Indexed: 12/21/2022]
Abstract
Abnormal visceral patterning has been known for centuries. However, it has not been associated with ciliary dysfunction until recently. Overlapping clinical entities including situs inversus, certain infertility disorders, as well as chronic respiratory infections have their roots in abnormal ciliary function. Current research focuses on causative factors and genes involved in signal transduction pathways that define ciliary function and structure, as well as treatment. In this review, attempts are made to outline selected, yet key topics related to ciliary function in health and disease.
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Dickinson S, Carr S, de Zoysa J, Barratt J. Cystic renal disease presenting in pregnancy: a novel presentation of oral-facial-digital syndrome type 1. Clin Kidney J 2008; 1:23-25. [PMID: 30792778 PMCID: PMC6375236 DOI: 10.1093/ndtplus/sfm012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2007] [Accepted: 10/15/2007] [Indexed: 01/31/2023] Open
Affiliation(s)
- Steven Dickinson
- The John Walls Renal Unit, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK
| | - Susan Carr
- The John Walls Renal Unit, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK
| | - Janak de Zoysa
- Department of Renal Medicine, Auckland City Hospital, Park Road, Grafton, Auckland, Private Bag 92024, New Zealand
| | - Jonathan Barratt
- The John Walls Renal Unit, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK
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Thauvin-Robinet C, Cossée M, Cormier-Daire V, Van Maldergem L, Toutain A, Alembik Y, Bieth E, Layet V, Parent P, David A, Goldenberg A, Mortier G, Héron D, Sagot P, Bouvier AM, Huet F, Cusin V, Donzel A, Devys D, Teyssier JR, Faivre L. Clinical, molecular, and genotype-phenotype correlation studies from 25 cases of oral-facial-digital syndrome type 1: a French and Belgian collaborative study. J Med Genet 2006; 43:54-61. [PMID: 16397067 PMCID: PMC2564504 DOI: 10.1136/jmg.2004.027672] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Oral-facial-digital syndrome type 1 (OFD1) is characterised by an X linked dominant mode of inheritance with lethality in males. Clinical features include facial dysmorphism with oral, tooth, and distal abnormalities, polycystic kidney disease, and central nervous system malformations. Large interfamilial and intrafamilial clinical variability has been widely reported, and 18 distinct mutations have been previously reported within OFD1. A French and Belgian collaborative study collected 25 cases from 16 families. OFD1 was analysed using direct sequencing and phenotype-genotype correlation was performed using chi2 test. X inactivation studies were performed on blood lymphocytes. In 11 families, 11 novel mutations, including nine frameshift, one nonsense, and one missense mutation were identified, which spanned nine different exons. A combination of our results with previously reported cases showed that the majority of mutations (65.5%) was located in exons 3, 8, 9, 13, and 16. There was phenotype-genotype correlation between (a) polycystic kidney disease and splice mutations; (b) mental retardation and mutations located in exons 3, 8, 9, 13, and 16; and (c) tooth abnormalities and mutations located in coiled coil domains. Comparing the phenotype of the families with a pathogenic mutation to families with absence of OFD1 mutation, polycystic kidneys and short stature were significantly more frequent in the group with no OFD1 mutation, whereas lingual hamartomas were significantly more frequent in the group with OFD1 mutation. Finally, an X inactivation study showed non-random X inactivation in a third of the samples. Differential X inactivation between mothers and daughters in two families with high intrafamilial variability was of particular interest. Slight phenotype-genotype correlations were established, and X inactivation study showed that skewed X inactivation could be partially involved in the pathogenesis of intrafamilial clinical variability.
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42
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Guay-Woodford LM. Renal cystic diseases: diverse phenotypes converge on the cilium/centrosome complex. Pediatr Nephrol 2006; 21:1369-76. [PMID: 16823577 DOI: 10.1007/s00467-006-0164-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2006] [Revised: 03/22/2006] [Accepted: 03/22/2006] [Indexed: 12/31/2022]
Abstract
Inherited renal cystic diseases constitute an important set of single-gene disorders that frequently progress to end stage renal disease (ESRD). Transmitted as autosomal dominant, autosomal recessive, or X-linked traits, renal cystic diseases are phenotypically diverse with respect to age at onset, rate of disease progression, and associated extra-renal manifestations. These disorders involve defects in a set of gene products commonly referred to as cystoproteins that, while functionally distinct, appear to co-localize, at least in part, with the cilia/centrosome complex. Therefore, investigations are increasingly focused on the role of this complex in the pathogenesis of renal cystic disease. Sorting out the functional relationship between these cystoproteins and the cilia/centrosome complex will undoubtedly provide a better understanding of renal cystic disease pathogenesis and, potentially, identify new targets for therapeutic intervention.
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Affiliation(s)
- Lisa M Guay-Woodford
- Departments of Medicine, Pediatrics, and Genetics, Division of Genetic and Translational Medicine, University of Alabama at Birmingham, 1530 3rd Avenue South 19th Street, Birmingham, AL 35294, USA.
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Toprak O, Uzum A, Cirit M, Esi E, Inci A, Ersoy R, Tanrisev M, Ok E, Franco B. Oral-facial-digital syndrome type 1, Caroli's disease and cystic renal disease. Nephrol Dial Transplant 2005; 21:1705-9. [PMID: 16384823 DOI: 10.1093/ndt/gfk013] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Omer Toprak
- Department of Nephrology, Medical School of Ege University, Izmir, Turkey.
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Abstract
Cystic kidney disorders are one of the leading causes of end-stage renal disease. Numerous experimental animal models have been used to understand the disease pathogenesis. Recent advancements in this field have provided a surprising finding: that many of the proteins associated with cystic kidney disease localize to a nearly forgotten organelle, the primary cilium.
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Affiliation(s)
- Qihong Zhang
- Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
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Nowaczyk MJM, Zeesman S, Whelan DT, Wright V, Feather SA. Oral-facial-digital syndrome VII is oral-facial-digital syndrome I: a clarification. Am J Med Genet A 2004; 123A:179-82. [PMID: 14598343 DOI: 10.1002/ajmg.a.20215] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
We report on further clinical findings in the one single family in the literature classified as oral-facial-digital (OFD) type VII in order to demonstrate that the diagnosis in this kindred should, in fact, be OFD type I. The mother and the daughter described in the original report have since developed polycystic kidney disease. In addition, the daughter recently had a daughter of her own with central nervous system, oral and digital anomalies. Linkage studies have shown that all the affected women share the same haplotype across the previously identified region Xp22.2p22.3 to which OFD I maps. Although the pedigree was too small for a significant lod score, the combination of clinical and molecular information clearly shows that the disease in this family is OFD I. We report this family in order to clarify and simplify the classification of the oral-facial-digital syndrome spectrum and to recommend the removal of OFD VII from the classification system of the oral-facial-digital syndromes.
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Affiliation(s)
- Malgorzata J M Nowaczyk
- Department of Pediatrics, McMaster University Medical Center, 1200 Main Street West, Hamilton, Ontario, Canada L8S 4J9.
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46
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Morisawa T, Yagi M, Surono A, Yokoyama N, Ohmori M, Terashi H, Matsuo M. Novel double-deletion mutations of the OFD1 gene creating multiple novel transcripts. Hum Genet 2004; 115:97-103. [PMID: 15221448 DOI: 10.1007/s00439-004-1139-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2004] [Accepted: 04/21/2004] [Indexed: 10/26/2022]
Abstract
Oral-facial-digital syndrome type 1 (OFD1) is an X-linked dominant disease characterized by malformations of the face, oral cavity, and digits. Thus far, 18 small mutations in the OFD1 gene have been reported. Here, we describe, in one Japanese sporadic female OFD1 case, the presence of a novel pair of deletion mutations: a 4,094-bp deletion encompassing exon 7 to intron 9, and a 14-bp deletion in intron 9, both of which are present in her paternal X-chromosome. The first deletion, the largest known to affect OFD1, was revealed by identifying four novel transcripts that all lacked exons 7-9. The most likely cause of the double deletion is two unequal recombinations between homologous sequences. Identification of the 4,094-bp deletion was made possible only by analyzing OFD1 mRNA, underscoring the utility of mRNA analysis in the mutational analysis of OFD1.
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Affiliation(s)
- Takeshi Morisawa
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho, Chuo, 650-0017, Kobe, Japan
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47
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Driva T, Franklin D, Crawford PJM. Variations in expression of oral-facial-digital syndrome (type I): report of two cases. Int J Paediatr Dent 2004; 14:61-8. [PMID: 14706030 DOI: 10.1111/j.1365-263x.2004.00503.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Two case reports are presented, both clearly demonstrating the diagnosis of oral-facial-digital syndrome, type I, but widely different in the expression of the condition. The first patient showed only mild expression of the syndrome. On examination at the age of 4 years there were no obvious extra oral signs, intraoral findings included the presence of supernumeraries in the primary dentition, spacing in two areas and the presence of an extra frenum. The second can be considered as a more severe case. This patient had many of the typical manifestations, including frontal bossing, a degree of zygomatic hypoplasia and clinodactyly. Orally, the most striking finding was a bilateral cleft palate which had not been diagnosed prior to examination at the age of 6 years. Other findings included multiple frena and a bifid tongue.
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Affiliation(s)
- T Driva
- Child Dental Health, Department of Oral Dental Sciences, Dental Hospital, University of Bristol, Bristol, UK.
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Ferrante MI, Barra A, Truong JP, Banfi S, Disteche CM, Franco B. Characterization of the OFD1/Ofd1 genes on the human and mouse sex chromosomes and exclusion of Ofd1 for the Xpl mouse mutant. Genomics 2003; 81:560-9. [PMID: 12782125 DOI: 10.1016/s0888-7543(03)00091-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Oral-facial-digital type 1 (OFD1) syndrome is an X-linked dominant condition characterized by malformations of the face, oral cavity, and digits. The responsible gene, OFD1, maps to human Xp22 and has an unknown function. We isolated and characterized the mouse Ofd1 gene and showed that it is subject to X-inactivation, in contrast to the human gene. Furthermore, we excluded a role for Ofd1 in the pathogenesis of the spontaneous mouse mutant Xpl, which had been proposed as a mouse model for this condition. Comparative sequence analysis demonstrated that OFD1 is conserved among vertebrates and absent in invertebrates. This analysis allowed the identification of evolutionarily conserved domains in the protein. Finally, we report the identification of 18 apparently nonfunctional OFD1 copies, organized in repeat units on the human Y chromosome. These degenerate OFD1-Y genes probably derived from the ancestral Y homologue of the X-linked gene. The high level of sequence identity among the different units suggests that duplication events have recently occurred during evolution.
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Affiliation(s)
- Maria I Ferrante
- Telethon Institute of Genetics and Medicine, 80131 Naples, Italy
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Lin BPJ, Lin MIJ, Berlocher WC. Clinical manifestations of terminal osseous dysplasia and pigmentary defects in a young girl. ORAL SURGERY, ORAL MEDICINE, ORAL PATHOLOGY, ORAL RADIOLOGY, AND ENDODONTICS 2003; 95:607-13. [PMID: 12738953 DOI: 10.1067/moe.2003.109] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Terminal osseous dysplasia and pigmentary defects is a rare X-linked dominant disorder with prenatal male lethality. Affected females display multiple systemic abnormalities such as limb deformities and pigmented lesions of the face and scalp. Phenotypic expression of the syndrome varies among the affected individuals. In this case report, we describe the syndromic dental and oral abnormalities in a female child aged 3 and 1/2 years. A widened bigonial width of the mandible and a brachyfacial pattern are observed. Intraoral findings include multiple frenulae, shallow mucobuccal fold, hypodontia, conical incisors, and other developmental structural defects.
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Affiliation(s)
- Brent P J Lin
- Department of Pediatric Dentistry, The University of Texas Health Science Center at San Antonio, Dental School - MSC 7888, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
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Romio L, Wright V, Price K, Winyard PJD, Donnai D, Porteous ME, Franco B, Giorgio G, Malcolm S, Woolf AS, Feather SA. OFD1, the gene mutated in oral-facial-digital syndrome type 1, is expressed in the metanephros and in human embryonic renal mesenchymal cells. J Am Soc Nephrol 2003; 14:680-9. [PMID: 12595504 DOI: 10.1097/01.asn.0000054497.48394.d2] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Oral-facial-digital syndrome type 1 (OFD1) causes polycystic kidney disease (PKD) and malformations of the mouth, face and digits. Recently, a gene on Xp22, OFD1, was reported to be mutated in a limited set of OFD1 patients. This study describes mutation analysis in six further OFD1 families. Additionally, gene expression was sought in human development. In two OFD1 kindreds affected by PKD, a frameshift mutation and a splice-site mutation were detected. In four apparently sporadic cases, three frameshift and a missense mutation were found. Using RT-PCR of RNA from first-trimester normal human embryos, both alternative splice forms of mRNA (OFD1a and OFD1b) were found to be widely expressed in organogenesis. Northern blot detected OFD1 mRNA in metanephros, brain, tongue, and limb, all organs affected in the syndrome. A polyclonal antibody directed to a C-terminal OFD1a epitope detected a 120-kD protein in the metanephros and in human renal mesenchymal cell lines. In normal human embryos, OFD1a immunolocalized to the metanephric mesenchyme, oral mucosa, nasal and cranial cartilage, and brain. Moreover, using normal human renal mesenchymal cell lines, the immunoreactive protein colocalized with gamma-tubulin, suggesting that OFD1 is associated with the centrosome. First, it is concluded that OFD1 mutations would generally be predicted to result in unstable transcripts or nonfunctional proteins. Second, OFD1 is expressed in human organogenesis; on the basis of the metanephric expression pattern, the results suggest that OFD1 plays a role in differentiation of metanephric precursor cells.
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Affiliation(s)
- Leila Romio
- Nephro-Urology Unit, Institute of Child Health, University College London, England.
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