Autosomal dominant polycystic kidney disease: molecular genetics and molecular pathogenesis

Mutations in three different genes, PKD1, PKD2 and PKD3, can cause a very s imilar clinical picture of the autosomal dominant form of polycystic kidney disease (ADPKD). Apparently, mutations in the PKD3 gene, which is still un mapped, are very rare, whereas PKD1 defects account for about 85% of cases. Although ADPKD is a frequent monogenic disorder affecting approximately 1: 1000 individuals in the Caucasian population, progress in understanding its pathology was somewhat slow until relatively recently when the PKD1 and PK D2 genes were mapped and cloned. They are both large, being approximately 5 2 kb and 68 kb in length respectively, and in addition, PKD1 is fairly comp lex, thus complicating mutation detection. The gene products, polycystin-1 and polycystin-2, are trans-membranous glycoproteins and are considered to be involved in signalling pathways, in cooperation with additional partners . Immunostaining studies in both humans and mice have revealed information regarding the localization of polycystins and their role in the development and maintenance of nephrons. Recent experimentation from various laborator ies has shown that loss of heterozygosity and acquired somatic second hits may account, at least paltry, for the inter- and intrafamilial phenotypic h eterogeneity of the disease, while at the same time, the existence of ether modifying loci is also hypothesized. The two-kit hypothesis is admittedly a very attractive one in that it can explain many of the features of the di sease, whereas recent data regarding a trans-heterozygous model for cystoge nesis adds to the complexity of the molecular mechanisms that can lead to p athogenesis.