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The Clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients
Author(s) -
Ikeda Masaki,
Sharma Vikram,
Mark Sumi S.,
Rogaeva Ekaterina A.,
Poorkaj Parvoneh,
Sherrington Robin,
Nee Linda,
Tsuda Takehide,
Oda Nobuhito,
Watanabe Mitsunori,
Aoki Masashi,
Shoji Mikio,
Abe Koji,
Itoymia Yasuto,
Hirai Shurisaku,
Schellenberg Gerard D.,
Bird Thomas D.,
GeorgeHyslop P. H. St
Publication year - 1996
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410400614
Subject(s) - missense mutation , genetics , exon , mutation , phenotype , biology , presenilin , alzheimer's disease , gene , pathology , disease , medicine
We report the clinical and neuropathologic phenotypes associated with two different missense mutations in the presenilin 1 (PS‐1) gene in Japanese patients with early‐onset familial Alzheimer's disease (FAD). In the Ah4/JPN1 pedigree a missense mutation (C→T) was found at nucleotide 1102, which is predicted to cause an alanine‐to‐valine missense substitution at codon 260. In this family, the disease had a mean age of onset of 40.3 years and an indolent course (range, 8–19 years). Neuropathologic studies in 3 members of this pedigree showed widespread senile plaques, neurofibrillary tangles, and neuronal loss, as well as abundant perivascular subpial amyloid deposits in the Virchow‐Robin spaces and the presence of Pick‐like intraneuronal inclusions in the dentate gyrus. In the second pedigree, transmitting a C→T nucleotide substitution at position 1027, leading to the missense mutation of alanine to valine at codon 285, the disease had a later onset (mean, 51 years) but a more rapid course. Comparison of the disease phenotypes associated with other missense mutations in exon 9 of PS‐1 reveals no clinical or pathological phenotype, which uniquely distinguishes Alzheimer's disease associated with PS‐1 mutations from other forms of early‐onset FAD, implying that direct mutation screening is required to identify these cases.