Zubenko G S, Farr J, Stiffler J S, Hughes H B, Kaplan B B
Department of Psychiatry, Western Psychiatric Institute and Clinic, School of Medicine, University of Pittsburgh, Pennsylvania 15213.
J Neuropathol Exp Neurol. 1992 Jul;51(4):459-63. doi: 10.1097/00005072-199207000-00008.
Three missense mutations in exon 17 of the beta-amyloid precursor protein (APP) gene have been reported to cosegregate in families with early onset Alzheimer's disease (AD). All three mutations result in amino acid substitutions at codon 717 and may produce AD by altering the structure of the transmembrane domain of APP. Alternatively, the mutations may destabilize the stem of a putative iron-responsive element (IRE) in which they lie and confer pathogenicity by inactivating this negative regulatory element. We have detected a clinically-silent mutation in codon 716 that would also be expected to disrupt the putative IRE but results in no amino acid substitution. This result strongly suggests that the missense mutations at codon 717 produce AD by altering the amino acid sequence of APP rather than the IRE. Furthermore, the identification of a clinically-silent mutation among four point mutations that span only three nucleotides of exon 17 suggests that this region may be a mutational "hot" spot.
据报道，β-淀粉样前体蛋白（APP）基因第17外显子中的三个错义突变在早发性阿尔茨海默病（AD）家族中呈共分离现象。所有这三个突变均导致第717密码子处的氨基酸替换，并且可能通过改变APP跨膜结构域的结构而引发AD。另外，这些突变可能会破坏它们所在的假定铁反应元件（IRE）茎的稳定性，并通过使这个负调控元件失活而赋予致病性。我们检测到第716密码子处有一个临床沉默突变，预计该突变也会破坏假定的IRE，但不会导致氨基酸替换。这一结果强烈表明，第717密码子处的错义突变是通过改变APP的氨基酸序列而非IRE来引发AD的。此外，在仅跨越第17外显子三个核苷酸的四个点突变中鉴定出一个临床沉默突变，这表明该区域可能是一个突变“热点”。
