Publicaciones científicas

Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease

Porath B (1), Gainullin VG (1), Cornec-Le Gall E (2), Dillinger EK (3), Heyer CM (1), Hopp K (4), Edwards ME (1), Madsen CD (1), Mauritz SR (1), Banks CJ (1), Baheti S (5), Reddy B (6), Herrero JI (7), Bañales JM (8), Hogan MC (1), Tasic V (9), Watnick TJ (10), Chapman AB (6), Vigneau C 11, Lavainne F (12), Audrézet MP (13), Ferec C (13), Le Meur Y (14), Torres VE (1); Genkyst Study Group, HALT Progression of Polycystic Kidney Disease Group; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease, Harris PC (15).
(1) Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
(2) 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.
(3) Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
(4) 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.
(5) Division of Biostatistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.
(6) Section of Nephrology, University of Chicago, Chicago, IL 60637, USA.
(7) 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.
(8) 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.
(9) Department of Pediatric Nephrology, University Children's Hospital, Skopje 1010, Macedonia.
(10) Division of Nephrology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
(11) Department of Nephrology, University Hospital, Rennes, Bretagne 35000, France.
(12) Department of Nephrology, University Hospital, Nantes, Pays De La Loire 44000, France.
(13) INSERM 1078, Department of Molecular Genetics, Université de Bretagne Occidentale, Brest, Brittany 29200, France.
(14) Department of Nephrology, University Hospital, Brest, Brittany 29200, France.
(15) Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA 

Revista: American Journal of Human Genetics

Fecha: 01-jun-2016

Hepatología

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.

CITA DEL ARTÍCULO  Am J Hum Genet. 2016 Jun 2;98(6):1193-1207. doi: 10.1016/j.ajhg.2016.05.004.

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