title: Genetics and pathogenesis of autosomal dominant polycystic kidney disease: 20 years on.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Brest, France; Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale, Brest, France; Service de Néphrologie, Hémodialyse et Transplantation Rénale, Centre Hospitalier Régional Universitaire, Hôpital de la Cavale Blanche, Brest, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Cornec-Le Gall
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Audrézet
authors.forename: Yannick
authors.initials: Y
authors.lastname: Le Meur
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
mesh_terms: D005838:Genotype; D006801:Humans; D008954:Models, Biological; D009030:Mosaicism; D009154:Mutation; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D050396:TRPP Cation Channels / Q000235:genetics
chemical_list: D050396:TRPP Cation Channels
keywords: ADPKD; PKD1; PKD2; genetic mosaicism; genotype-phenotype correlation; haploinsufficiency; renal cystogenesis; somatic mutation