Novel frameshift mutations near short simple repeats

Citation
Wh. Van Den Hurk et al., Novel frameshift mutations near short simple repeats, J BIOL CHEM, 276(15), 2001, pp. 11496-11498
Citations number
16
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
276
Issue
15
Year of publication
2001
Pages
11496 - 11498
Database
ISI
SICI code
0021-9258(20010413)276:15<11496:NFMNSS>2.0.ZU;2-Z
Abstract
In patients with Alzheimer's disease or Down's syndrome, the cerebellar cor tex exhibits protein deposits in neurofibrillary tangles and neuritic plaqu es. Recently, the deposits have been shown to contain protein fragments of ubiquitin-B and amyloid precursor protein (APP) with an aberrant carboxyl t erminus resulting from frameshift mutations (dinucleotide deletions; Delta GU or Delta GA) in or adjacent to GAGAG motifs in their mRNAs, a process re ferred to as molecular misreading. We have now used a bacterial expression system with the green fluorescent protein as a reporter to screen gene tran scripts from aged controls, Alzheimer's disease, and Down's syndrome for mo lecular misreading. Novel frameshift mutations at a number of locations in the transcripts of the ubiquitin-B and APP genes were discovered (Delta GA, DeltaG, Delta GU, Delta GG, Delta CA, Delta AU, DeltaA, Delta AA, DeltaC, DeltaU, and insertion of an A). Interestingly, most mutations were in close proximity of short simple repeats (GAGAG, GGUGGU, GAGACACACA, UCAUCAUCA, C AAACAAA, and GAAGAAGAA), demonstrating that the GAGAG motif does not consti tute the only hot spot for transcriptional errors. Unlike the previously de tected aberrant APP fragments, some of the novel ones have the potential to generate the neurotoxic peptide beta -amyloid, We conclude that during agi ng molecular misreading is a widespread phenomenon.