A novel presenilin 1 mutation (F388L) identified in a Chinese family with early-onset Alzheimer's disease.

ABSTRACT

A subset of Alzheimer's disease (AD) occurrence shows autosomal dominant, familial inheritance patterns. Such familial AD (FAD) are caused by mutations in APP, PSEN1, and PSEN2 genes, which encode amyloid-ß (Aß) precursor protein, presenilin 1 (PS1), and presenilin 2 (PS2), respectively. Here, we report a novel PSEN1 mutation (c.1164C > G, p.F388L, mutation nomenclature according to National Center for Biotechnology Information Reference Sequence NM_000021.3) occurring in a Chinese family with early-onset AD and cosegregating with affected family members. The average age at onset of this family was 43 years. The F388L mutation locates adjacent to the critical catalytic aspartate site (D385) of PS1. Overexpression of the F388L mutant significantly increased Aß42 secretion and the ratio of Aß42/Aß40 when compared with wild type PS1, consisting with the notion that FAD-associated PS1 mutations induce disease pathogenesis by increasing Aß42/Aß40 ratio. Our results identify a novel pathogenic PS1 F388L mutation in a Chinese FAD family.