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Identification of a cis ‐acting element involved in the regulation of BACE1 mRNA alternative splicing
Author(s) -
Mowrer Karen R.,
Wolfe Michael S.
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06026.x
Subject(s) - minigene , rna splicing , exon , alternative splicing , exonic splicing enhancer , exon skipping , biology , splice site mutation , genetics , microbiology and biotechnology , gene , rna
β‐site APP cleaving enzyme 1 (BACE1) is the transmembrane aspartyl protease that catalyzes the first cleavage step during proteolysis of the β‐amyloid precursor protein, a process involved in the pathogenesis of Alzheimer disease. BACE1 pre‐mRNA undergoes complex alternative splicing, and cis ‐acting elements important for its regulation have not been identified. We constructed and compared several BACE1 minigenes and found that BACE1 sequence from exon 3 through exon 5 was required for minigenes to undergo correct splicing. Minigene splicing was validated by showing specific splicing inhibition upon splice site mutation. Furthermore, we showed that mutation of the minigene at a predicted exonic splicing enhancer in exon 4 of BACE1 increased exon 4 skipping. Therefore, we have for the first time found evidence of a regulatory site involved in BACE1 alternative splicing, and these data indicate that minor sequence changes can dramatically alter BACE1 alternative splicing.