RGD Reference Report - The gene encoding nicastrin, a major gamma-secretase component, modifies risk for familial early-onset Alzheimer disease in a Dutch population-based sample.

General

The gene encoding nicastrin, a major gamma-secretase component, modifies risk for familial early-onset Alzheimer disease in a Dutch population-based sample.
Authors:	Dermaut, Bart Theuns, Jessie Sleegers, Kristel Hasegawa, Hiroshi Van den Broeck, Marleen Vennekens, Krist'l Corsmit, Ellen St George-Hyslop, Peter Cruts, Marc van Duijn, Cornelia M Van Broeckhoven, Christine
Citation:	Dermaut B, etal., Am J Hum Genet. 2002 Jun;70(6):1568-74. Epub 2002 Apr 24.
RGD ID:	13801052
Pubmed:	PMID:11992262 (View Abstract at PubMed)
PMCID:	PMC379144 (View Article at PubMed Central)
Nicastrin regulates gamma-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 beta 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 epsilon4 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 gamma-secretase dysfunction in the etiology of familial EOAD.

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
Alzheimer's disease	no_association	IAGP		13801052	DNA:missense mutation: :417N>Y (human)	RGD
Alzheimer's disease	onset	IAGP		13801052	DNA:SNPs and haplotype:introns:multiple	RGD
Alzheimer's disease	no_association	ISO	NCSTN (Homo sapiens)	13801052; 13801052	DNA:missense mutation: :417N>Y (human)	RGD
Alzheimer's disease	onset	ISO	NCSTN (Homo sapiens)	13801052; 13801052	DNA:SNPs and haplotype:introns:multiple	RGD

Objects Annotated

Genes (Rattus norvegicus)

Ncstn (nicastrin)

Genes (Mus musculus)

Ncstn (nicastrin)

Genes (Homo sapiens)

NCSTN (nicastrin)

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The gene encoding nicastrin, a major gamma-secretase component, modifies risk for familial early-onset Alzheimer disease in a Dutch population-based sample.