SEGREGATION OF A MISSENSE MUTATION IN THE AMYLOID PRECURSOR PROTEIN GENE WITH FAMILIAL ALZHEIMERS-DISEASE
SEGREGATION OF A MISSENSE MUTATION IN THE AMYLOID PRECURSOR PROTEIN GENE WITH FAMILIAL ALZHEIMERS-DISEASE
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DOI：
10.1038/349704a0
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发表时间：
1991-02-21
期刊：
影响因子：
64.8
通讯作者：
HARDY, J
中科院分区：
文献类型：
--
作者：
GOATE, A;CHARTIERHARLIN, MC;HARDY, J
一个与家族性阿尔茨海默病（AD）分离的基因座已被定位于21号染色体（参考文献1），靠近淀粉样前体蛋白（APP）基因2-5。已报道APP基因和AD基因座之间的突变6-8，这似乎排除了它作为引起家族性AD的突变位点。但最近对大量AD家族的遗传分析表明，这种疾病是异质性的。晚发性AD家族与21号染色体标记9、10无连锁关系。部分早发性AD家系与21号染色体标记连锁，部分家系与8、9、11号染色体标记不连锁。这导致了即使在早发性家族性AD中也存在非等位基因遗传异质性的建议8，9。为了避免异质性给遗传分析带来的问题，我们在一个经尸检证实的AD家系中研究了AD和21号染色体长臂沿着标记的共分离。在这里，我们证明，在这个亲属，这表明连锁21号染色体标记，有一个APP基因的点突变。该突变导致靠近β-淀粉样肽羧基末端的氨基酸取代（瓦尔--> Ile）。筛查其他家族性AD病例发现了第二个发生这种变异的无关家族。这表明某些AD病例可能是由APP基因突变引起的。
A LOCUS segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21 (ref. 1), close to the amyloid precursor protein (APP) gene 2-5. Recombinants between the APP gene and the AD locus have been reported 6-8 which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous 9. Families with late-onset AD do not show linkage to chromosome 21 markers 9,10. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not 8,9,11. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD 8,9. To avoid problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val --> Ile) close to the carboxy terminus of the beta-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene.