A PATHOGENIC MUTATION FOR PROBABLE ALZHEIMERS-DISEASE IN THE APP GENE AT THE N-TERMINUS OF BETA-AMYLOID
A PATHOGENIC MUTATION FOR PROBABLE ALZHEIMERS-DISEASE IN THE APP GENE AT THE N-TERMINUS OF BETA-AMYLOID
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DOI：
10.1038/ng0892-345
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发表时间：
1992-08-01
期刊：
影响因子：
30.8
通讯作者：
LANNFELT, L
中科院分区：
文献类型：
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作者：
MULLAN, M;CRAWFORD, F;LANNFELT, L
β -淀粉样前体蛋白（APP）基因外显子17的第717密码子突变先前已被证明在一些家族中与早发性阿尔茨海默病相关联。我们在来自瑞典的两个大型（可能相关）早发性阿尔茨海默病家族中发现了外显子16的第670和671密码子（APP 770转录本）的双突变，该突变与疾病共分离。从正常序列发生的两个碱基对颠换（G到T，A到C）预示着APP转录本的第670和671密码子处的赖氨酸变为天冬酰胺以及甲硫氨酸变为亮氨酸的氨基酸替换。这种突变发生在β -淀粉样蛋白的氨基末端，可能具有致病性，因为它发生在该分子的内体/溶酶体切割位点或其附近。因此，APP中的致病性突变围绕着β -淀粉样蛋白序列。
Mutations at codon 717 in exon 17 of the beta-amyloid precursor protein (APP) gene have previously been shown to segregate with early onset Alzheimer's disease in some families. We have identified a double mutation at codons 670 and 671 (APP 770 transcript) in exon 16 which co-segregates with the disease in two large (probably related) early-onset Alzheimer's disease families from Sweden. Two base pair transversions (G to T, A to C) from the normal sequence predict Lys to Asn and Met to Leu amino acid substitutions at codons 670 and 671 of the APP transcript. This mutation occurs at the amino terminal of beta-amyloid and may be pathogenic because it occurs at or close to the endosomal/lysosomal cleavage site of the molecule. Thus, pathogenic mutations in APP frame the beta-amyloid sequence.