Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease
| Autor: | Cécile Vigneau, Binu Porath, Elizabeth K. Dillinger, Saurabh Baheti, Marie C. Hogan, José Ignacio Herrero, Sarah R. Mauritz, Katharina Hopp, Emilie Cornec-Le Gall, Peter C. Harris, Vladimir G. Gainullin, Christina M. Heyer, Vicente E. Torres, Velibor Tasic, Marie Pierre Audrézet, Marie E. Edwards, Terry Watnick, Charles D. Madsen, Arlene B. Chapman, Yannick Le Meur, Frédéric Lavainne, Carly J. Banks, Claude Férec, Jesus M. Banales, Bharathi V. Reddy |
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| Přispěvatelé: | Division of Nephrology and Hypertension, Mayo Clinic, Service de néphrologie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biochemistry and Molecular Biology, University of Southampton, Mayo Clinic [Rochester], University of Chicago, Clínica Universidad de Navarra [Pamplona], Department of Liver and Gastrointestinal Diseases (Biodonista Health Research Institute), Department of Liver and Gastrointestinal Diseases, Department of Pediatric Nephrology, University Children’s Hospital, Division of Nephrology, University of Maryland [Baltimore], Section of Nephrology University of Chicago, CHU Pontchaillou [Rennes], Service de Néphrologie [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, This study received support from NIDDK grant DK058816, the Mayo PKD Translational Center (DK090728), an American Heart Association postdoctoral fellowship (B.P.), the Mayo Clinic Nephrology Training Grant (T32DK007013 to V.G.G.), an American Society of Nephrology (ASN) Foundation Kidney Research Fellowship (E.C.-L.G.) and Ben J. Lipps Research Fellowship (K.H.), the Mayo Graduate School (E.K.D.), the Zell Family Foundation, and Robert M. and Billie Kelley Pirnie. The CRISP and HALT-PKD studies were supported by NIDDK cooperative agreements (DK056943, DK056956, DK056957, DK056961, DK062410, DK062408, DK062402, DK082230, DK062411, and DK062401), National Center for Research Resources General Clinical Research Centers, and National Center for Advancing Translational Sciences Clinical and Translational Science Awards. The Genkyst cohort was supported by National Plans for Clinical Research, Groupement Interrégional de Recherche Clinique et d’Innovation (GIRCI Grand Ouest), and the French Society of Nephrology., CHRU - Service de néphrologie, dialyse et transplantation rénale, Hospital Donostia. CIBERehd, CHRU Brest - Service de Nephrologie (CHU - BREST - Nephrologie), Universidade de Aveiro, National Physical Laboratory [Teddington] (NPL), Cancer du rein : bases moléculaires de la tumorogenèse, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]-Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Michel, Geneviève, EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Candidate gene 030232 urology & nephrology Fluorescent Antibody Technique urologic and male genital diseases [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology 0302 clinical medicine Polycystic kidney disease Genetics(clinical) Child Genetics (clinical) Cells Cultured Microscopy Confocal Cysts Polycystic liver disease Liver Diseases Middle Aged Polycystic Kidney Autosomal Dominant female genital diseases and pregnancy complications 3. Good health Pedigree Female Adult medicine.medical_specialty [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics Biology Article 03 medical and health sciences SEC63 Internal medicine medicine Genetics Humans Immunoprecipitation Amino Acid Sequence Aged [SDV.GEN]Life Sciences [q-bio]/Genetics PKD1 Sequence Homology Amino Acid PRKCSH Genetic heterogeneity alpha-Glucosidases medicine.disease [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology Transplantation 030104 developmental biology Endocrinology [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics Mutation CRISPR-Cas Systems |
| Zdroj: | American Journal of Human Genetics American Journal of Human Genetics, Elsevier (Cell Press), 2016, 98 (6), pp.1193-1207. ⟨10.1016/j.ajhg.2016.05.004⟩ |
| ISSN: | 0002-9297 1537-6605 |
| Popis: | International audience; Autosomal-dominant polycystic kidney disease (ADPKD) is a common, progressive, adult-onset disease that is an important cause of end-stage renal disease (ESRD), which requires transplantation or dialysis. Mutations in PKD1 or PKD2 (∼85% and ∼15% of resolved cases, respectively) are the known causes of ADPKD. Extrarenal manifestations include an increased level of intracranial aneurysms and polycystic liver disease (PLD), which can be severe and associated with significant morbidity. Autosomal-dominant PLD (ADPLD) with no or very few renal cysts is a separate disorder caused by PRKCSH, SEC63, or LRP5 mutations. After screening, 7%-10% of ADPKD-affected and ∼50% of ADPLD-affected families were genetically unresolved (GUR), suggesting further genetic heterogeneity of both disorders. Whole-exome sequencing of six GUR ADPKD-affected families identified one with a missense mutation in GANAB, encoding glucosidase II subunit α (GIIα). Because PRKCSH encodes GIIβ, GANAB is a strong ADPKD and ADPLD candidate gene. Sanger screening of 321 additional GUR families identified eight further likely mutations (six truncating), and a total of 20 affected individuals were identified in seven ADPKD- and two ADPLD-affected families. The phenotype was mild PKD and variable, including severe, PLD. Analysis of GANAB-null cells showed an absolute requirement of GIIα for maturation and surface and ciliary localization of the ADPKD proteins (PC1 and PC2), and reduced mature PC1 was seen in GANAB(+/-) cells. PC1 surface localization in GANAB(-/-) cells was rescued by wild-type, but not mutant, GIIα. Overall, we show that GANAB mutations cause ADPKD and ADPLD and that the cystogenesis is most likely driven by defects in PC1 maturation. |
| Databáze: | OpenAIRE |
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