Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17

错义突变 外显子 τ蛋白 遗传学 生物 失智症 17号染色体(人) RNA剪接 突变 神经病理学 剪接 选择性拼接 基因 痴呆 染色体 阿尔茨海默病 核糖核酸 医学 疾病 病理
作者
Mike Hutton,Corinne Lendon,Patrizia Rizzu,Matt Baker,Susanne Froelich,Henry Houlden,Stuart Pickering‐Brown,Sumi Chakraverty,Adrian M. Isaacs,Andrew Grover,Jennifer Hackett,Jennifer Adamson,Sarah Lincoln,Dennis W. Dickson,Peter J. Davies,Ronald C. Petersen,Martijn Stevens,Esther de Graaff,Erwin Wauters,Jeltje van Baren
出处
期刊:Nature [Nature Portfolio]
卷期号:393 (6686): 702-705 被引量:3414
标识
DOI:10.1038/31508
摘要

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)(1-9), historically termed Pick's disease(10). Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics(1-8,12). Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon in. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10 (ref. 13). This causes more frequent usage of the 5' splice site and an increased proportion of tan transcripts that include exon 10. The increase in exon 10(+) messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17 (refs 12, 14).
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