Genetic Analysis Of Klotho In Diseases Of Aging

根据对Klotho突变小鼠的研究，Klotho基因在抑制几种不同的衰老表型方面发挥了作用。Klotho基因缺陷纯合的小鼠表现出一种与人类衰老非常相似的症状，包括动脉粥样硬化、骨质疏松症、肺气肿、不孕不育和皮肤萎缩。我们已经在杰克逊实验室的一组特征良好的小鼠品系中寻找了klotho基因的序列变异。对这20个菌株的klotho基因的每个外显子进行了测序。在该小组的16个实验室来源的近交系中，没有发现任何变异。然而，在4个野生来源的自交系中，发现了多个变异，其中5个导致了氨基酸替换。还鉴定了可能影响基因产物的一个缺失和一个插入。实时RT-PCR分析Klotho基因在野生菌株中的表达表明，其中一个基因变异与较高的基因表达水平有关。对这一发现的临床意义的调查正在进行中。我们已经获得了IRB批准的一项临床方案，该方案将在Batlimore纵向衰老研究的参与者中寻找Klotho基因的功能变异。这项分析才刚刚开始，在接下来的一年里，我们将寻求确定Klotho基因的特定变种，与特定的人类衰老疾病有关，包括动脉粥样硬化、II型糖尿病、骨质疏松症和骨关节炎。

The Klotho gene is known to play a role in suppressing several different aging phenotypes, based on studies in the klotho mutant mouse. Mice homozygous for defects in the klotho gene exhibit a syndrome that closely resembles human aging, including atherosclerosis, osteoporosis, emphysema, infertility and skin atrophy. We have looked for sequence variation in the klotho gene in a paenl of well-characterized mouse strains from the Jackson Laboratory. Each exon of the klotho gene was sequenced in each of these 20 strains. No variation was found in any of the 16 laboratory derived inbred stains in the panel. However, among the 4 wild-derived inbred strains, multiple variants were found, of which five resulted in amino acid substitutions. One deletion and one insertion likely to influence the gene product were also identified. Real-time RT-PCR analysis of klotho gene expression in the wild-derived strains has shown that one of the gene variants is associated with a higher gene expression level than the others. Investigation of the clinical significance of this finding is ongoing. We have received IRB approval of a clinical protocol to look for functional variants of the Klotho gene among participants in the Batlimore Longitudinal Study on Aging. This analysis has just begun, and over the next year we will be seeking to identify specific variants of the Klotho gene associated with specific human disorders of aging, including atherosclerosis, type II diabetes, osteoporosis and osteoarthritis.