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The Gene Encoding Nicastrin, a Major γ-Secretase Component, Modifies Risk for Familial Early-Onset Alzheimer Disease in a Dutch Population-Based Sample

Authors
Journal
The American Journal of Human Genetics
0002-9297
Publisher
Elsevier
Publication Date
Volume
70
Issue
6
Identifiers
DOI: 10.1086/340732
Disciplines
  • Biology
  • Medicine

Abstract

Nicastrin regulates γ-secretase cleavage of the amyloid precursor protein by forming complexes with presenilins, in which most mutations causing familial early-onset Alzheimer disease (EOAD) have been found. The gene encoding nicastrin (NCSTN) maps to 1q23, a region that has been linked and associated with late-onset Alzheimer disease (LOAD) in various genome screens. In 78 familial EOAD cases, we found 14 NCSTN single-nucleotide polymorphisms (SNPs): 10 intronic SNPs, 3 silent mutations, and 1 missense mutation (N417Y). N417Y is unlikely to be pathogenic, since it did not alter amyloid β secretion in an in vitro assay and its frequency was similar in case and control subjects. However, SNP haplotype estimation in two population-based series of Dutch patients with EOAD ( n=116) and LOAD ( n=240) indicated that the frequency of one SNP haplotype (HapB) was higher in the group with familial EOAD (7%), compared with the LOAD group (3%) and control group (3%). In patients with familial EOAD without the APOE ε4 allele, the HapB frequency further increased, to 14%, resulting in a fourfold increased risk (odds ratio = 4.1; 95% confidence interval 1.2–13.3; P=.01). These results are compatible with an important role of γ-secretase dysfunction in the etiology of familial EOAD.

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