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Lookup NU author(s): Dr Christopher Morris
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We previously described a splice donor site mutation in intron 4 of presenilin-1 (PSEN1) in two patients with autopsy-confirmed early-onset Alzheimer's disease (AD), Here we provide evidence that the intron 4 mutation is present in four additional unrelated early-onset AD cases, that the mutation segregates in an autosomal dominant manner and that all cases have one common ancestor. We demonstrate that the intron 4 mutation produces three different transcripts, two deletion transcripts (Delta 4 and Delta 4(cryptic)) and one insertion transcript (ins(TAC)), by aberrant splicing, The deletion transcripts result in the formation of C-truncated (similar to 7 kDa) PSEN1 proteins while the insertion transcript produces a full-length PSEN1 with one extra amino acid (Thr) inserted between codons 113 and 114 (PSEN1 T113-114ins). The truncated proteins were not detectable in vivo in brain homogenates or lymphoblast lysates of mutation carriers. In vitro HEK-293 cells overexpressing Delta 4, Delta 4(cryptic) or ins(TAC) PSEN1 cDNAs showed increased A beta 42 secretion (similar to 3.4 times) only for the insertion cDNA construct. Increased A beta 42 production was also observed in brain homogenates, Our data indicate that in the case of intron 4 mutation, the AD pathophysiology results from the presence of the PSEN1 T113-114ins protein comparable with cases carrying dominant PSEN1 missense mutations.
Author(s): Morris CM; De Jonghe C; Cruts M; Rogaeva EA; Tysoe C; Singleton A; Vanderstichele H; Meschino W; Dermaut D; Vanderhoeven I; Backhovens H; Vanmechelen E; Hardy J; Rubinsztein DC; St George-Hyslop PH; Van Broeckhoven C
Publication type: Article
Publication status: Published
Journal: Human Molecular Genetics
Year: 1999
Volume: 8
Issue: 8
Pages: 1529-1540
Print publication date: 01/08/1999
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/hmg/8.8.1529
DOI: 10.1093/hmg/8.8.1529
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