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Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased Aβ42 secretion

(1999) HUMAN MOLECULAR GENETICS. 8(8). p.1529-1540
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Abstract
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.

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Chicago
De Jonghe, Chris, Marc Cruts, Ekaterina A Rogaeva, Carolyn Tysoe, Andrew Singleton, Hugo Vanderstichele, Wendy Meschino, et al. 1999. “Aberrant Splicing in the Presenilin-1 Intron 4 Mutation Causes Presenile Alzheimer’s Disease by Increased Aβ42 Secretion.” Human Molecular Genetics 8 (8): 1529–1540.
APA
De Jonghe, C., Cruts, M., Rogaeva, E. A., Tysoe, C., Singleton, A., Vanderstichele, H., Meschino, W., et al. (1999). Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer’s disease by increased Aβ42 secretion. HUMAN MOLECULAR GENETICS, 8(8), 1529–1540.
Vancouver
1.
De Jonghe C, Cruts M, Rogaeva EA, Tysoe C, Singleton A, Vanderstichele H, et al. Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer’s disease by increased Aβ42 secretion. HUMAN MOLECULAR GENETICS. 1999;8(8):1529–40.
MLA
De Jonghe, Chris, Marc Cruts, Ekaterina A Rogaeva, et al. “Aberrant Splicing in the Presenilin-1 Intron 4 Mutation Causes Presenile Alzheimer’s Disease by Increased Aβ42 Secretion.” HUMAN MOLECULAR GENETICS 8.8 (1999): 1529–1540. Print.
@article{3201184,
  abstract     = {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       = {De Jonghe, Chris and Cruts, Marc and Rogaeva, Ekaterina A and Tysoe, Carolyn and Singleton, Andrew and Vanderstichele, Hugo and Meschino, Wendy and Dermaut, Bart and Vanderhoeven, Inge and Backhovens, Hubert and Vanmechelen, Eugeen and Morris, Christopher M and Hardy, John and Rubinsztein, David C and St George-Hyslop, Peter H and Van Broeckhoven, Christine},
  issn         = {0964-6906},
  journal      = {HUMAN MOLECULAR GENETICS},
  language     = {eng},
  number       = {8},
  pages        = {1529--1540},
  title        = {Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased A\ensuremath{\beta}42 secretion},
  url          = {http://dx.doi.org/10.1093/hmg/8.8.1529},
  volume       = {8},
  year         = {1999},
}

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