Genetics and Pathogenesis of Autosomal Dominant Polycystic Kidney Disease: 20 Years On

• Published in: Human mutation Vol. 35; no. 12; pp. 1393 - 1406
• Main Authors: Cornec-Le Gall, Emilie, Audrézet, Marie-Pierre, Le Meur, Yannick, Chen, Jian-Min, Férec, Claude
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-12-2014; Hindawi Limited
• Subjects: ADPKD; genetic mosaicism; Genetics; Genotype; Genotype & phenotype; genotype-phenotype correlation; haploinsufficiency; Humans; Kidney diseases; Models, Biological; Mosaicism; Mutation; Pathogenesis; Phenotype; PKD1; PKD2; Polycystic Kidney, Autosomal Dominant - genetics; renal cystogenesis; somatic mutation; TRPP Cation Channels - genetics; ADPKD; haploinsufficiency; genetic mosaicism; genotype-phenotype correlation; PKD2; somatic mutation; PKD1; renal cystogenesis
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22708

ABSTRACT
Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disorder, is characterized by the progressive development and expansion of bilateral fluid‐filled cysts derived from the renal tubule epithelial cells. Although typically leading to end‐stage renal disease in late middle age, ADPKD represents a continuum, from neonates with hugely enlarged cystic kidneys to cases with adequate kidney function into old age. Since the identification of the first causative gene (i.e., PKD1, encoding polycystin 1) 20 years ago, genetic studies have uncovered a large part of the key factors that underlie the phenotype variability. Here, we provide a comprehensive review of these significant advances as well as those related to disease pathogenesis models, including mutation analysis of PKD1 and PKD2 (encoding polycystin 2), current mutation detection rate, allelic heterogeneity, genotype and phenotype relationships (in terms of three different inheritance patterns: classical autosomal dominant inheritance, complex inheritance, and somatic and germline mosaicism), modifier genes, the role of second somatic mutation hit in renal cystogenesis, and findings from mouse models of polycystic kidney disease. Based upon a combined consideration of the current knowledge, we attempted to propose a unifying framework for explaining the phenotype variability in ADPKD.
ADPKD (Autosomal Dominant Polycystic Kidney Disease) is characterized by the development of fluid‐filled cysts in the kidneys. Half of the patients developed end‐stage renal disease before the age of 65. This article provides a comprehensive review of the recent advances in the genetics and pathogenesis of ADPKD.