A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families
A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families
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DOI：
10.1001/jama.286.18.2257
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发表时间：
2001-11-14
影响因子：
120.7
通讯作者：
Mayeux, R
中科院分区：
文献类型：
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作者：
Athan, ES;Williamson, J;Mayeux, R
背景 阿尔茨海默病 (AD) 的遗传决定因素尚未在加勒比西班牙裔群体中得到全面检查，该群体是美国的一个群体，与非西班牙裔白人相比，阿尔茨海默病的发病率更高。目的：鉴定与加勒比裔西班牙裔家族性早发 AD 相关的基因中的变异等位基因。设计和设置 1998-2001 年在纽约州的 AD 研究中心进行的基于家庭的病例系列 纽约州约克和多米尼加共和国的诊所。患者在 206 个有 2 名或以上在世成员患有 AD 的 206 个加勒比西班牙裔家庭中，有 19 个家庭 (9.2%) 至少有 1 人在 55 岁之前发病。 主要结果测量 对来自先证者的早老素 1 基因的整个编码区以及淀粉样蛋白前体蛋白基因的外显子 16 和 17 进行了测序。 19个家庭和 结果 在来自 19 个家族中的 8 个家族 (42%) 的 23 个个体中观察到，G 到 C 核苷酸的变化导致早老素 1 外显子 7 中密码子 206 (Gly206Ala) 处的甘氨酸 - 丙氨酸氨基酸取代。通过对纽约市 319 名无关个体的相应基因进行测序，还发现了一名患有 Gly206Ala 突变和早发家族性疾病的加勒比西班牙裔个体。公共基因数据库中未发现 Gly206Ala 突变，但在来自 4 个西班牙裔家庭的 5 名个体中发现了该突变，这些人患有 AD，需进行基因检测。这些家族的成员彼此之间没有血缘关系，但所有测试的 Gly206Ala 突变携带者在 2 个附近的微卫星多态性上共享一个变异等位基因，表明有一个共同的祖先。淀粉样蛋白前体蛋白基因未发现突变。结论 19个不相关的加勒比西班牙裔早发家族性AD家族中有8个发现Gly206Ala突变。这种基因变化可能是加勒比西班牙裔人群中早发家族性 AD 的普遍原因。
Context Genetic determinants of Alzheimer disease (AD) have not been comprehensively examined in Caribbean Hispanics, a population in the United States in whom the frequency of AD is higher compared with non-Hispanic whites.Objective: Ta identify variant alleles in genes related to familial early-onset AD among Caribbean Hispanics.Design and Setting Family-based case series conducted in 1998-2001 at an AD research center in New York, NY, and clinics in the Dominican Republic.Patients Among 206 Caribbean Hispanic families with 2 or more living members with AD who were identified, 19 (9.2%) had at least 1 individual with onset of AD before the age of 55 years.Main Outcome Measure The entire coding region of the presenilin 1 gene and exons 16 and 17 of the amyloid precursor protein gene were sequenced in probands from the 19 families and their living relatives.Results A G-to-C nucleotide change resulting in a glycine-alanine amino acid substitution at codon 206 (Gly206Ala) in exon 7 of presenilin 1 was observed in 23 individuals from 8 (42%) of the 19 families. A Caribbean Hispanic individual with the Gly206Ala mutation and early-onset familial disease was also found by sequencing the corresponding genes of 319 unrelated individuals in New York City. The Gly206Ala mutation was not found in public genetic databases but was reported in 5 individuals from 4 Hispanic: families, with AD referred for genetic testing. None of the members of these families were related to one another, yet all carriers of the Gly206Ala mutation tested shared a variant allele at 2 nearby microsatellite polymorphisms, indicating a common ancestor. No mutations were found in the amyloid precursor protein gene.Conclusions The Gly206Ala mutation was found in 8 of 19 unrelated Caribbean Hispanic families with early-onset familial AD. This genetic change may be a prevalent cause of early-onset familial AD in the Caribbean Hispanic population.