What Is the Role of Somatic Mutation in Autosomal Dominant Polycystic Kidney Disease?

Abstract

A 50% dosage reduction of gene product, known as haploinsufficiency, as found in heterozygotes with an inactivating mutation, is not usually associated with a detectable physiologic effect. Consequently, either loci associated with dominant disease are those rare ones that are sensitive to haploinsufficiency, or an additional mechanism plays a role to enhance the effect of the single mutant allele. In the case of autosomal dominant polycystic kidney disease (ADPKD), adult-onset disease is characterized by focal cyst development and expansion as a result of heterozygous mutation in PKD1 or PKD2 . In mice, homozygous inactivating mutations to either Pkd1 or Pkd2 results in embryonic lethality with the development of renal and pancreatic cysts from embryonic day 13.5.1,2 Humans with two fully penetrant mutations are also thought to have a nonviable phenotype. The wide range of human mutations causing ADPKD, approximately 70% of which are clearly inactivating, and the lack of clear genotype–phenotype correlations suggest that a dominant negative mechanism, whereby the mutant product adversely affects the function of the normal ADPKD allele product, is unlikely to be important in the human disease.3 Rather, a widely accepted view is that ADPKD is recessive at the cellular level and that cysts develop clonally from a tubular cell only once the cell has acquired a second, somatic mutation to inactivate the remaining normal allele. There are considerable data to support this two-hit hypothesis for cystogenesis in ADPKD. This includes the demonstration of deletion (loss of heterozygosity) or inactivating point mutations to the remaining normal PKD1 or PKD2 allele in epithelial cyst linings isolated from single cysts, in either the kidney or the liver.4–8 In addition, there is evidence for the clonality of cysts.7 Further data come from a Pkd2 mouse model ( Pkd2 WS25) that is prone …