Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease.
摘要：
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 inPKD1orPKD2(∼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 byPRKCSH,SEC63, orLRP5mutations. 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 inGANAB, encoding glucosidase II subunit α (GIIα). BecausePRKCSHencodes GIIβ,GANABis 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 ofGANAB-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 inGANAB+/−cells. PC1 surface localization inGANAB−/−cells was rescued by wild-type, but not mutant, GIIα. Overall, we show thatGANABmutations cause ADPKD and ADPLD and that the cystogenesis is most likely driven by defects in PC1 maturation.
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DOI：
10.1016/j.ajhg.2016.05.004
被引量：
年份：
2016
Elsevier
万方医学
掌桥科研
万方医学
dx.doi.org
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