Somatic Inactivation of Pkd2 Results in Polycystic Kidney Disease

TLDR

Autosomal dominant polycystic kidney disease is caused by germline mutations in PKD2. A mutant exon 1 was inserted alongside the wild‑type exon 1 at the mouse Pkd2 locus, creating an unstable allele that undergoes somatic inactivation via intragenic homologous recombination to generate a true null allele. Mice carrying the mutant allele develop kidney and liver cysts indistinguishable from human ADPKD, with cysts arising from tubular cells that lose Pkd2 expression, demonstrating that somatic loss of Pkd2 is necessary and sufficient for cyst formation and indicating a cellular recessive mechanism.

Abstract

Germline mutations in PKD2 cause autosomal dominant polycystic kidney disease. We have introduced a mutant exon 1 in tandem with the wild-type exon 1 at the mouse Pkd2 locus. This is an unstable allele that undergoes somatic inactivation by intragenic homologous recombination to produce a true null allele. Mice heterozygous and homozygous for this mutation, as well as Pkd+/- mice, develop polycystic kidney and liver lesions that are indistinguishable from the human phenotype. In all cases, renal cysts arise from renal tubular cells that lose the capacity to produce Pkd2 protein. Somatic loss of Pkd2 expression is both necessary and sufficient for renal cyst formation in ADPKD, suggesting that PKD2 occurs by a cellular recessive mechanism.