TY - JOUR
T1 - Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease
AU - Porath, Binu
AU - Gainullin, Vladimir G.
AU - Cornec-Le Gall, Emilie
AU - Dillinger, Elizabeth K.
AU - Heyer, Christina M.
AU - Hopp, Katharina
AU - Edwards, Marie E.
AU - Madsen, Charles D.
AU - Mauritz, Sarah R.
AU - Banks, Carly J.
AU - Baheti, Saurabh
AU - Reddy, Bharathi
AU - Herrero, José Ignacio
AU - Bañales, Jesús M.
AU - Hogan, Marie C.
AU - Tasic, Velibor
AU - Watnick, Terry J.
AU - Chapman, Arlene B.
AU - Vigneau, Cécile
AU - Lavainne, Frédéric
AU - Audrézet, Marie Pierre
AU - Ferec, Claude
AU - Le Meur, Yannick
AU - Torres, Vicente E.
AU - Harris, Peter C.
N1 - Funding Information:
We thank the families and coordinators for involvement in the study, the Exome Aggregation Consortium, Tatyana Masyuk, and other HALT Progression of Polycystic Kidney Disease (HALT-PKD) and Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) investigators: Drs. Grantham, Yu, and Winklehofer (Kansas Medical Center), Bae, Abebe, and Landsittel (University of Pittsburgh), Schrier and Brosnahan (University of Colorado Denver), Perrone and Miskulin (Tufts University), Braun (Cleveland Clinic), Steinman (Beth Israel Deaconess Medical Center), Mrug (University of Alabama at Birmingham), Rahbari-Oskoui (Emory University), Bennett (Legacy Health, Portland), Flessner (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK]), Moore (Carolinas HealthCare, Charlotte), and Czarnecki (Brigham and Women’s Hospital). 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.
Publisher Copyright:
© 2016 American Society of Human Genetics.
PY - 2016/6/2
Y1 - 2016/6/2
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2016.05.004
DO - 10.1016/j.ajhg.2016.05.004
M3 - Article
C2 - 27259053
AN - SCOPUS:84971570661
VL - 98
SP - 1193
EP - 1207
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 6
ER -