A novel presenilin 1 mutation (F388L) identified in a Chinese family with early-onset Alzheimer's disease.
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-β (Aβ) 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 Aβ42 secretion and the ratio of Aβ42/Aβ40 when compared with wild type PS1, consisting with the notion that FAD-associated PS1 mutations induce disease pathogenesis by increasing Aβ42/Aβ40 ratio. Our results identify a novel pathogenic PS1 F388L mutation in a Chinese FAD family.
Department of Neurology, First Affiliated Hospital, Xiamen University, Xiamen, Fujian, China.
Yihong
Y
Zhan
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China; Shenzhen Research Institute of Xiamen University, Shenzhen, China. Electronic address: honghua@xmu.edu.cn.
Honghua
H
Zheng
Department of Neurology, First Affiliated Hospital, Xiamen University, Xiamen, Fujian, China.
Chen
C
Wang
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China.
Zhouyi
Z
Rong
Department of Neurology, First Affiliated Hospital, Xiamen University, Xiamen, Fujian, China.
Naian
N
Xiao
Department of Neurology, First Affiliated Hospital, Xiamen University, Xiamen, Fujian, China. Electronic address: qilinma@yeah.net.
Qilin
Q
Ma
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China. Electronic address: yunzhang@xmu.edu.cn.
Yun-Wu
YW
Zhang
D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000235:genetics; D056726:Genetic Association Studies; D005820:Genetic Testing; D006801:Humans; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics*; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
Chinese family; Early-onset Alzheimer's disease; PSEN1 mutation