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Coding mutations in SORL1 and Alzheimer disease.


ABSTRACT: OBJECTIVE:Common single nucleotide polymorphisms in the SORL1 gene have been associated with late onset Alzheimer disease (LOAD), but causal variants have not been fully characterized nor has the mechanism been established. The study was undertaken to identify functional SORL1 mutations in patients with LOAD. METHODS:This was a family- and cohort-based genetic association study. Caribbean Hispanics with familial and sporadic LOAD and similarly aged controls were recruited from the United States and the Dominican Republic, and patients with sporadic disease of Northern European origin were recruited from Canada. Prioritized coding variants in SORL1 were detected by targeted resequencing and validated by genotyping in additional family members and unrelated healthy controls. Variants transfected into human embryonic kidney 293 cell lines were tested for A?40 and A?42 secretion, and the amount of the amyloid precursor protein (APP) secreted at the cell surface was determined. RESULTS:Seventeen coding exonic variants were significantly associated with disease. Two rare variants (rs117260922-E270K and rs143571823-T947M) with minor allele frequency (MAF)?

SUBMITTER: Vardarajan BN 

PROVIDER: S-EPMC4367199 | BioStudies | 2015-01-01

REPOSITORIES: biostudies

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