Mutations in a NIMA-related kinase gene, Nek1, cause pleiotropic effects including a progressive polycystic kidney disease in mice

摘要

We previously have described a mouse model for polycystic kidney disease (PKD) caused by either of two mutations, kat or kat~2J, that map to the same locus on chromosome 8. The homozygous mutant animals have a latent onset. slowly progressing form of PKD with renal pathology similar to the human autosomal-dominant PKD. In addition, the mutant animals show pleiotropic effects that include facial dysmorphism. dwarfing, male sterility, anemia, and cystic choroid plexus. We previously fine-mapped the kat~2J mutation to a genetic distance of 0.28 ± 0.12 centimorgan between D8Mit128 and D8Mit129. To identify the underlying molecular defect in this locus, we constructed an integrated genetic and physical map of the critical region surrounding the kat~2J mutation. Cloning and expression analysis of the transcribed sequences from this region identified Nek1, a NIMA (never in mitosis A)-related kinase as a candidate gene. Further analysis of the Nek1 gene from both kat/kat and kat~2J/kat~2J mutant animals identified a partial internal deletion and a single-base insertion as the molecular basis for these mutations. The complex pleiotropic phenotypes seen in the ho- mozygous mutant animals suggest that the NEK1 protein partici- Pates in different signaling pathways to regulate diverse cellular processes. Our findings identify a previously unsuspected role for Nek1 in the kidney and open a new avenue for studying cysto- genesis and identifying possible modes of therapy.