A NOVEL FRAMESHIFT MUTATION INDUCED BY AN ADENOSINE INSERTION IN THE POLYCYSTIC KIDNEY-DISEASE-2 (PKD2) GENE

Autosomal dominant polycystic kidney disease (ADPKD) is one of the mos t common Mendelian disorders and is genetically heterogeneous. Linkage studies have shown that the majority (similar to 85%) of ADPKD cases are due to mutations in PKD1 on chromosome 16p13.3, while mutations in PKD3 on chromosome 4q21-q23 are thought to account for most of the re maining cases. In this report, we describe the mutation in a large fou r-generation ADPKU family (TOR-PKD77) which we had mapped to the PKD2 locus by linkage analysis. In this family, we screened for mutations b y directly sequencing two nested RT-PCR fragments (PKD2N1 and PKD2N2) that cover similar to 90% of the PKD2 open reading frame. In the affec ted members, we identified a novel single adenosine insertion (2160Ins A) in the PKD2N2 fragment. This mutation occurred in the polyadenosine tract (nt2152-2159) of exon 11 and is predicted to result in a frames hift with premature translation termination of the PKD2 product, polyc ystin 2, immediately after codon 723. The truncated polycystin 2 is pr edicted to lack the calcium-binding EF-hand domain and two cytoplasmic domains required for the homodimerization of polycystin 2 with itself and for the heterodimerization of polycystin 2 with polycystin 1.