Genetic Analysis of Disease Modifiers of the Cystogenic Kinase Nek8

描述（由申请人提供）：小鼠模型的遗传分析是研究修饰位点如何导致表型表达变异的一种手段。我们已经表明，多囊肾病（PKD）的进展在少年囊肾（杰克）突变可以受到不同菌株背景的影响。我们已经将其中一个修饰位点定位在4号染色体近端，该区域先前被发现可以改变两种不同小鼠PKD突变的疾病进展。同一位点可以影响三种不同小鼠PKD突变的疾病进展，这一证据具有相当重要的意义，因为这表明该基因可能影响PKD的严重程度，而不考虑其原因。因此，这个基因座代表了人类PKD治疗干预的潜在靶点。我们建议继续在同源菌株中对该PKD修饰子进行高分辨率定位。我们还建议通过分析基因靶向突变小鼠来检测PKD修饰子候选位点。最后，我们提出了一种新的分析策略，使用远交种小鼠，这将有可能提高修饰位点的遗传定位的速度和分辨率。

DESCRIPTION (provided by applicant): Genetic analysis in mouse models is a means to investigate how modifying loci cause variation in phenotypic expression. We have shown that polycystic kidney disease (PKD) progression in the juvenile cystic kidney (jck) mutation can be influenced by different strain backgrounds. We have localized one of these modifier loci to proximal chromosome 4, in a region previously found to modify disease progression in two different mouse PKD mutations. The evidence that the same locus can influence disease progression in three different murine PKD mutations is of considerable significance, since this suggests this gene might influence PKD severity irrespective of its cause. As such, this locus represents a potential target for therapeutic intervention in human PKD. We propose to continue our ongoing high-resolution localization of this PKD modifier in congenic strains. We also propose to test PKD modifier candidate loci by analysis of genetically targeted mutant mice. Lastly, we propose a novel strategy of analysis using outbred mice that will potentially increase the speed and resolution of genetic localization of modifying loci. PUBLIC HEALTH RELEVANCE: It is well known that the same underlying genetic defect in the PKD gene can have different degrees of severity, presumably as a function of the genetic background of the affected individual. This has led to the recognition of potential importance of modifier loci, which can influence the expression of the PKD defect. Positional cloning of such loci may suggest alternative avenues of therapeutic intervention.