Somatic PKD2 Mutations in Individual Kidney and Liver Cysts Support a “Two-Hit” Model of Cystogenesis in Type 2 Autosomal Dominant Polycystic Kidney Disease

Abstract

Abstract. An intriguing feature of autosomal dominant polycystic kidney disease (ADPKD) is the focal and sporadic formation of renal and extrarenal cysts. Recent documentation of somatic PKD1 mutations in cystic epithelia of patients with germ-line PKD1 mutations suggests a “two-hit” model for cystogenesis in type 1 ADPKD. This study tests whether the same mechanism for cystogenesis might also occur in type 2 ADPKD. Genomic DNA was obtained from 54 kidney and liver cysts from three patients with known germ-line PKD2 mutations, using procedures that minimize contamination of cells from noncystic tissue. Using intragenic and microsatellite markers, these cyst samples were screened for loss of heterozygosity. The same samples were also screened for somatic mutations in five of the 15 exons in PKD2 by single-stranded conformational polymorphism analysis. Loss of heterozygosity was found in five cysts, and unique intragenic mutations were found in seven other cysts. In 11 of these 12 cysts, it was also determined that the somatic mutation occurred nonrandomly in the copy of PKD2 inherited from the unaffected parent. These findings support the “two-hit” model as a unified mechanism for cystogenesis in ADPKD. In this model, the requirement of a somatic mutation as the rate-limiting step for individual cyst formation has potential therapeutic implications.

Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway

“…PC2 also is present in the endoplasmic reticulum (ER) where it may function as either a calcium release channel or a regulator of the 1,4,5-trisphosphate receptor (IP 3 R) (10). Molecular genetic studies of human samples suggest that the disease is recessive on a cellular level, likely explaining the focal nature of cyst formation and the variable clinical presentation (11,12). ARPKD, on the other hand, has an estimated incidence of ~1:20,000 live births, presents primarily in infancy and childhood, and is typically more severe than ADPKD (13,14).…”

Germline Mutations for Kidney Volume in ADPKD

“…As intrafamilial phenotypic variability exists among patients with the same mutation, somatic inactivation of the remaining wild-type PKD1 or PKD2 allele is thought to be required to initiate ADPKD and to play a key role in patients with ADPKD (the 2-hit model of ADPKD). 38 , 39 , 40 As a result, most previous studies on ADPKD have focused on the second hit mechanism and have made remarkable progress in the genome studies of ADPKD; however, research on germline mutations or genetic background has not progressed extensively. Although the 2-hit model is an important mechanism of ADPKD, recent evidence has suggested that PKD progression or severity is influenced by the level of functional polycystins (haploinsufficiency/loss of function model).…”

Studying Kidney Diseases Using Organoid Models

“…Polycystic kidney disease (PKD) represents one of the most common monogenic kidney diseases, constituting approximately 3% of CKD cases. PKD can be mainly categorised into autosomal dominant (ADPKD) and autosomal recessive (ARPKD) ( Wilson, 2004 ), typically induced by germline mutation of PKD1 or PKD2 , and PKHD1 , respectively ( Qian et al, 1996 ; Pei et al, 1999 ). Because homozygous germline deletion of Pkd1 or Pkd2 in mice lead to embryonic lethality, conditional/kidney-specific knockout, and hypomorphic models are more suitable to investigate ADPKD pathogenesis ( Herron et al, 2002 ; Leeuwen et al, 2004 ; Piontek et al, 2004 ; Piontek et al, 2007 ; Yu et al, 2007 ; Takakura et al, 2008 ).…”