Genetic evidence for a trans-heterozygous model for cystogenesis in autosomal dominant polycystic kidney disease

Polycystic kidney disease (ADPKD) is a condition with an autosomal dominant mode of inheritance and adult onset. Two forms of the disease, ADPKD1 and ADPKD2, caused by mutations in PKD1 and PKD2, respectively, are very simila r, except that ADPKD1 patients run a more severe course. At the cellular le vel, ADPKD1 was first shown to be recessive, since somatic second hits are perhaps necessary for cyst formation. The near identical phenotype had sugg ested that ADPKD1 and ADPKD2 might have a similar pathogenesis and that the two gene products, polycystins 1 and 2, are part of a common developmental pathway. Work in transgenic mice showed that somatic toss of Pkd2 expressi on is necessary for renal cyst formation, and recently we showed that somat ic mutations inactivating the inherited healthy allele were present in 9 of 23 cysts from a human ADPKD2 kidney, supporting a two-hit loss-of-function model for ADPKD2 cystogenesis. Here, we provide the first direct genetic e vidence that polycystins 1 and 2 do interact, perhaps as part of a larger c omplex. In cystic DNA from a kidney of an ADPKD1 patient, we showed somatic mutations not only in the PKD1 gene of certain cysts, but also in the PKD2 gene of others, generating a trans heterozygous state with mutations in bo th genes. One mutation in PKD1 is of germinal nature and the mutation in th e PKD2 gene is of somatic nature. The implications of such a situation are enormous, not only for ADPKD, but also for many other conditions with pheno typic heterogeneity and age-dependent penetrance.