Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset Alzheimer's disease in Mexican families
Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset Alzheimer's disease in Mexican families
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DOI：
10.1007/s10048-006-0043-3
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发表时间：
2006-07-01
期刊：
影响因子：
2.2
通讯作者：
Elisa Alonso, Maria
中科院分区：
文献类型：
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作者：
Yescas, Petra;Huertas-Vazquez, Adriana;Elisa Alonso, Maria
阿尔茨海默病（Alzheimer's disease，AD）的病因复杂。迄今为止，在几个受AD影响的家族中的分子遗传学研究已经确定了与高度外显的早发性AD相关的三个基因：早老素1（PSEN 1）、早老素2（PSEN 2）和β-淀粉样前体蛋白（APP）;以及与晚发性AD相关的一个基因（载脂蛋白E）。通过基因组DNA的直接测序进行PSEN 1基因的分子分析。可能的创始人效应进行了研究分析两个高度多态性的微卫星标记侧翼的PSEN 1基因。分析了12个不相关的早发性AD墨西哥家庭。其中9个家系（75%）存在PSEN 1基因第12外显子的Ala 431 Glu突变，呈常染色体显性遗传。由于所有携带突变的家庭都来自哈利斯科州（位于墨西哥西部），因此假设存在创始人效应。微卫星单倍型分析表明，这9个基因组有共同的祖先。总之，Ala 431 Glu突变是墨西哥哈利斯科州家族中早发性家族性阿尔茨海默病的普遍原因。遗传学证据支持它是一个创始人突变，来自一个共同的祖先。这些研究结果具有重要的意义，及时诊断和遗传咨询的墨西哥家族性AD患者从哈利斯科。
The etiology of Alzheimer's disease (AD) is complex. To date, molecular genetic studies in several families affected with AD have identified three genes associated with highly penetrant early-onset AD: Presenilin 1 (PSEN1), Presenilin 2 (PSEN2) and beta-amyloid precursor protein (APP); and one gene (apolipoprotein E) associated with late-onset AD. Molecular analysis of the PSEN1 gene was performed by direct sequencing of genomic DNA. The possible founder effect was investigated analyzing two highly polymorphic microsatellite markers flanking the PSEN1 gene. Twelve unrelated Mexican families with early-onset AD were analyzed. The Ala431Glu mutation in exon 12 of PSEN1 was found in nine (75%) of these families, which segregated showing autosomal dominant inheritance. Because all families bearing the mutation are from the State of Jalisco (located in Western Mexico), a founder effect was hypothesized. Microsatellite haplotype analysis suggested a common ancestor in these nine kindreds. In conclusion, the Ala431Glu mutation is a prevalent cause of early-onset familial Alzheimer's disease in families from the State of Jalisco, Mexico. Genetic evidence supports that it is a founder mutation descending from a single common ancestor. These findings have important implications for prompt diagnosis and genetic counseling for Mexican patients with familial AD from Jalisco.