Somatic PKD2 mutations in individual kidney and liver cysts support a "two-hit" model of cystogenesis in type 2 autosomal dominant polycystic kidney disease

An intriguing feature of autosomal dominant polycystic kidney disease (ADPK D) is the focal and sporadic formation of renal and extrarenal cysts. Recen t documentation of somatic PKD1 mutations in cystic epithelia of patients w ith 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, us ing procedures that minimize contamination of cells from noncystic tissue. Using intragenic and microsatellite markers, these cyst samples were screen ed for loss of heterozygosity, The same samples were also screened for soma tic mutations in five of the 15 exons in PKD2 by single-stranded conformati onal 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 n onrandomly in the copy of PKD2 inherited from the unaffected parent. These findings support the "two-hit" model as a unified mechanism for cystogenesi s in ADPKD. In this model, the requirement of a somatic mutation as the rat e-limiting step for individual cyst formation has potential therapeutic imp lications.