Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in one of three genes: PKD1 on chromosome 16 accounts for similar to 85% o f cases whereas PKD2 on chromosome 4 accounts for similar to 15%, Mutations in the PKD3 gene are rare. All patients present with similar clinical phen otypes, and the cardinal symptom is the formation of fluid-filled cysts in the kidneys. Previous work has provided data supporting the notion that cys ts in ADPKD1 are focal in nature and form after loss of function of polycys tin 1, This became evident by demonstrating that the normal PKD1 allele was inactivated somatically by loss of heterozygosity or by mutagenesis in a s ubset of renal or liver cysts examined. We show in this report, for the fir st time, multiple novel somatic mutations within the PKD2 gene of epithelia l cells, in both kidneys of an ADPKD2 patient. From a total of 21 cysts exa mined, seven (33%) had the same C insertion within the inherited wild-type allele, In two other cysts, a nonsense mutation and a splice site AG deleti on had occurred in a PKD2 allele that could not be identified as the inheri ted wild-type or mutant. We suggest that the autosomal dominant form of ADP KD2 occurs by a cellular recessive mechanism, supporting a two-hit model fo r cyst formation.