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In affected members of a family with early-onset AD (104300), Ancolio et al. (1999) identified a mutation in the APP gene, resulting in a val715-to-met (V715M) substitution. Overexpression of V715M in human HEK293 cells and murine neurons reduced total A-beta production and increased the recovery of the physiologically secreted product, APP-alpha. The V715M mutation significantly reduced A-beta-40 secretion without affecting A-beta-42 production in HEK293 cells. However, a marked increase in N-terminally truncated A-beta ending at position 42 was observed, whereas its counterpart ending at position 40 was not affected. These results suggested that, in some cases, familial AD may be associated with a reduction in the overall production of A-beta, but may be caused by increased production of truncated forms of A-beta ending at position 42. This family with the V715M mutation was also reported by Campion et al. (1999), the same family having been ascertained through a population-based survey of early-onset Alzheimer disease.

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