Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region.
Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region.
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发表时间：
1992-11
影响因子：
9.8
通讯作者：
K. Kamino;H. T. Orr;H. Payami;Ellen M. Wijsman;M. E. Alonso;Stefan M. Pulst;L. Anderson;Sheldon O'dahl;E. Nemens;June A. White;A. Sadovnick;Melvyn J. Ball;J. Kaye;Andrew Warren;Melvin G. McInnis;S. Antonarakis;Julie R. Korenberg;V. Sharma;W. Kukull;Eric Larson;Leonard L. Heston;George M. Martin;Thomas D. Bird;G. D. Schellenberg
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作者：
K. Kamino;H. T. Orr;H. Payami;Ellen M. Wijsman;M. E. Alonso;Stefan M. Pulst;L. Anderson;Sheldon O'dahl;E. Nemens;June A. White;A. Sadovnick;Melvyn J. Ball;J. Kaye;Andrew Warren;Melvin G. McInnis;S. Antonarakis;Julie R. Korenberg;V. Sharma;W. Kukull;Eric Larson;Leonard L. Heston;George M. Martin;Thomas D. Bird;G. D. Schellenberg
大量的家族性阿尔茨海默病（FAD）激酶被检查，以确定淀粉样前体蛋白（APP）基因的突变是否可能导致这种疾病。先前的研究已经确定了APP密码子717处的三个突变是阿尔茨海默病（AD）的致病性。对受影响受试者的样本进行了APP基因外显子16和17的突变检查。直接测序和单链构象多态性分析相结合。散发性AD和正常对照组也采用同样的方法进行检测。鉴定了五种序列变体。APP密码子693处的一个变体导致Glu->Gly改变。这是与淀粉样变性-荷兰型Glu->Gln突变的遗传性脑出血相同的密码子。APP密码子708处的另一个单碱基变化没有改变该位点编码的氨基酸。在外显子17周围的内含子序列中发现了两个点突变和一个6-bp缺失。没有一种变体可以明确确定为FAD的原因。还通过检测FAD与紧密连锁于APP的高度多态性短串联重复标记（D21 S210）的连锁来分析较大的家族。对于所检测的家族组获得高度阴性的LOD分数，并且对于伏尔加德国人的连锁被正式排除在θ = 0.10之外，对于早发性非伏尔加德国人的连锁被正式排除在θ = 0.20之外，晚发型家族的θ = 0.10 FAD与APP着丝粒标记（D21 S1/S11，D21 S13和D21 S215）的连锁LOD评分在三个家族组中也为阴性。这些研究表明，APP突变只占FAD激酶的一小部分。
A large number of familial Alzheimer disease (FAD) kindreds were examined to determine whether mutations in the amyloid precursor protein (APP) gene could be responsible for the disease. Previous studies have identified three mutations at APP codon 717 which are pathogenic for Alzheimer disease (AD). Samples from affected subjects were examined for mutations in exons 16 and 17 of the APP gene. A combination of direct sequencing and single-strand conformational polymorphism analysis was used. Sporadic AD and normal controls were also examined by the same methods. Five sequence variants were identified. One variant at APP codon 693 resulted in a Glu-->Gly change. This is the same codon as the hereditary cerebral hemorrhage with amyloidosis-Dutch type Glu-->Gln mutation. Another single-base change at APP codon 708 did not alter the amino acid encoded at this site. Two point mutations and a 6-bp deletion were identified in the intronic sequences surrounding exon 17. None of the variants could be unambiguously determined to be responsible for FAD. The larger families were also analyzed by testing for linkage of FAD to a highly polymorphic short tandem repeat marker (D21S210) that is tightly linked to APP. Highly negative LOD scores were obtained for the family groups tested, and linkage was formally excluded beyond theta = .10 for the Volga German kindreds, theta = .20 for early-onset non-Volga Germans, and theta = .10 for late-onset families. LOD scores for linkage of FAD to markers centromeric to APP (D21S1/S11, D21S13, and D21S215) were also negative in the three family groups. These studies show that APP mutations account for AD in only a small fraction of FAD kindreds.