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

Abstract

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 kat͞kat 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 homozygous mutant animals suggest that the NEK1 protein participates 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 cystogenesis and identifying possible modes of therapy. P olycystic kidney disease (PKD) is the most common inherited nephropathy in humans (1). PKD is characterized by massive renal enlargement associated with the growth of fluidfilled intrarenal cysts. Genetic studies of inherited PKD in humans and animal models clearly have shown that mutations at multiple loci with different modes of inheritance result in various forms of PKD (2-7). In recent years, major advances have been made toward understanding the genetics of PKD. In humans, the PKD1 and PKD2 loci that cause autosomal-dominant PKD (ADPKD) and the murine orck locus that causes disease pathology similar to the human autosomal-recessive PKD (ARPKD) have been cloned. The PKD1 gene product, polycystin-1, encodes an integral membrane glycoprotein with significant homology to membrane proteins involved in cell-cell and͞or cell-matrix interactions (8). The PKD2 gene product, polycystin-2, is also an integral membrane protein with homology to the voltage-activated Ca 2ϩ channel ␣ 1E and the Na ϩ voltagedependent channels (9). Analysis of the primary sequence of the orck gene product reveals a protein containing 10 copies of an internally repeated, 34-aa (tetratricopeptide) motif that is found in a number of cell-cycle control proteins (10). Although the primary structure has predicted certain roles for these three proteins, their function still remains largely unknown. However, because patients with mutations in either PKD1 or PKD2 have a similar clinical phenotype and recent in vitro studies have shown that polycystin-1 and polycystin-2 interact via their Cterminal ...

Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy

“…Instead, in both cases polycystic kidney disease is a major or the sole phenotype, respectively (Upadhya et al, 2000;Liu et al, 2002). Consistent with the polycystic kidney disease, localization of these proteins to the centrosome and to the primary cilium (Mahjoub et al, 2005;Shalom et al, 2008;White and Quarmby, 2008), and ciliary phenotypes (Smith et al, 2006;Shalom et al, 2008) have been reported.…”

Members of the NIMA-related Kinase Family Promote Disassembly of Cilia by Multiple Mechanisms

“…Some NRKs participate in ciliary functions (reviewed by Quarmby and Mahjoub, 2005). Mutations in the vertebrate NRKs, Nek1 and Nek8, cause polycystic kidney disease in mice and zebrafish (Upadhya et al, 2000;Liu et al, 2002). The FA2 gene of Chlamydomonas encodes an NRK that is essential for flagellar autotomy and normal rate of disassembly (Mahjoub et al, 2002).…”

Nek11, a New Member of the NIMA Family of Kinases, Involved in DNA Replication and Genotoxic Stress Responses

“…Nek3 is a cytoplasmic protein relatively abundant at G 0 phase, but its function has not been established (13). Mutation in murine nek1 is involved in the Kat phenotype, including polycystic kidneys, dwarfism, male sterility, and facial dysmorphism (26), and nek4 is highly expressed in germinal cells similar to nek1 and nek2 (16,27,28), but functions of Nek1 and Nek4 are obscure. Nek6 and Nek7 are cytoplasmic proteins lacking the C-terminal regulatory domain (18) and function as putative regulators for p70 ribosomal S6 kinase (29).…”