Genetic Analysis Of Klotho In Diseases Of Aging

根据对Klotho突变小鼠的研究，Klotho基因已知在抑制几种不同的衰老表型中发挥作用。klotho基因缺陷的纯合子小鼠表现出一种与人类衰老非常相似的综合征，包括动脉粥样硬化、骨质疏松症、肺气肿、不孕症和皮肤萎缩。我们已经在一批来自杰克逊实验室的特征良好的小鼠品系中寻找klotho基因的序列变异。在这20个菌株中的每一个中对klotho基因的每个外显子进行测序。在该小组中的16个实验室来源的近交系菌株中没有发现任何变异。然而，在4个野生来源的近交系中，发现了多个变体，其中5个导致氨基酸替换。还鉴定了可能影响基因产物的一个缺失和一个插入。klotho基因在野生型菌株中表达的实时RT-PCR分析表明，其中一种基因变异与比其他基因更高的基因表达水平相关。目前正在研究这一发现的临床意义。我们已经收到了IRB批准的临床方案，以寻找Klotho基因的功能变异的参与者在Batlimore纵向研究老化。这项分析刚刚开始，在接下来的一年里，我们将寻求确定与特定人类衰老疾病相关的Klotho基因的特定变体，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.