Genetic studies of inherited polycystic kidney disease (PKD) in man and animal models have clearly shown that mutations at multiple loci result in various forms of PKD. In addition, genetic background or modifier genes appear to significantly alter the clinical manifestations and progression of PKD. Identification and characterization of the disease genes and their modifiers will provide a better understanding of the pathways and the cellular processes important in stabilizing this critical organ. The investigators have identified NIMA (Never in mitosis A) related kinase, Nekl, a dual specific protein kinase as the gene altered by the murine recessive kat, kat2J, kat3J mutations that leads to a latent onset slowly progressing form of PKD with renal pathology similar to the human autosomal dominant PKD. They have mapped modifier loci that alter the severity of the kidney disease caused by the loss of Nek1 function. Based on the clinical manifestations seen in the mutants due to the loss of Nekl function, they hypothesize that, in the kidney, the NEK1 protein belongs to a developmentally regulated signaling pathway that either directly or indirectly affects transport functions. A multidimensional approach to test this hypothesis and investigate the functional consequence of the absence of NEK1 by: analyzing the expression pattern, tissue distribution and renal subcellular localization of Nekl gene products in control and mutant animals during development, isolating protein factors that interact with NEKI using biochemical and genetic approaches, and assessing the effect of different domains of NEK1 on certain key kinase-signaling pathway. The nature of the interacting protein factor(s) and the key kinase-signaling pathway(s) influenced by the NEK1 protein will provide cues to the cellular programs regulated by the normal NEKI protein in the kidney. Thus, our findings have opened new avenues for studying renal cystogenesis and identifying possible modes of therapy to this devastating human disease.
