Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease.
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.
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
Binu
B
Porath
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
Vladimir G
VG
Gainullin
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA; INSERM 1078, Department of Molecular Genetics, Université de Bretagne Occidentale, Brest, Brittany 29200, France; Department of Nephrology, University Hospital, Brest, Brittany 29200, France.
Emilie
E
Cornec-Le Gall
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
Elizabeth K
EK
Dillinger
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
Christina M
CM
Heyer
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA; Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO 80202, USA.
Katharina
K
Hopp
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
Marie E
ME
Edwards
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
Charles D
CD
Madsen
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
Sarah R
SR
Mauritz
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
Carly J
CJ
Banks
Division of Biostatistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.
Saurabh
S
Baheti
Section of Nephrology, University of Chicago, Chicago, IL 60637, USA.
Bharathi
B
Reddy
Liver Unit, Clinica Universidad de Navarra, Pamplona, Navarra 31009, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid 28029, Spain; Instituto de Investigación Sanitaria de Navarra, Navarra 31008, Spain.
José Ignacio
JI
Herrero
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Ikerbasque, San Sebastián 20014, Spain.
Jesús M
JM
Bañales
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
Marie C
MC
Hogan
Department of Pediatric Nephrology, University Children's Hospital, Skopje 1010, Macedonia.
Velibor
V
Tasic
Division of Nephrology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
Terry J
TJ
Watnick
Section of Nephrology, University of Chicago, Chicago, IL 60637, USA.
Arlene B
AB
Chapman
Department of Nephrology, University Hospital, Rennes, Bretagne 35000, France.
Cécile
C
Vigneau
Department of Nephrology, University Hospital, Nantes, Pays De La Loire 44000, France.
Frédéric
F
Lavainne
INSERM 1078, Department of Molecular Genetics, Université de Bretagne Occidentale, Brest, Brittany 29200, France.
Marie-Pierre
MP
Audrézet
INSERM 1078, Department of Molecular Genetics, Université de Bretagne Occidentale, Brest, Brittany 29200, France.
Claude
C
Ferec
Department of Nephrology, University Hospital, Brest, Brittany 29200, France.
Yannick
Y
Le Meur
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
Vicente E
VE
Torres
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: harris.peter@mayo.edu.
Peter C
PC
Harris
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D064113:CRISPR-Cas Systems; D002478:Cells, Cultured; D002648:Child; D003560:Cysts / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D008107:Liver Diseases / Q000235:genetics*; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000473:pathology; D017386:Sequence Homology, Amino Acid; D000520:alpha-Glucosidases / Q000235:genetics*
C034251:4-nitrophenyl-alpha-glucosidase; D000520:alpha-Glucosidases