Objective: To identify SORL1 risk genotypes that determine receptor protein expression in the human brain.
Design: DNA, RNA, and proteins were extracted from brain autopsies of Alzheimer disease cases and used for SORL1 genotyping, RNA profiling, and SORLA protein quantification, respectively.
Setting: Specimens were provided by the MRC London Brain Bank for Neurodegenerative Diseases and the Netherlands Brain Bank.
Subjects: Brain autopsy material (frontal cortex) from 88 confirmed cases of sporadic Alzheimer disease.
Results: Our studies identified a SORL1 haplotype in the 3' gene region consisting of single-nucleotide polymorphisms rs1699102 and rs2070045 that is associated with poor receptor expression in the brain of patients with Alzheimer disease. These gene variations alter the SORL1 transcript sequence, resulting in a change from frequent to rare codon usage in the minor risk genotype. Studies in cultured cells confirm less efficient translation of the minor receptor transcripts into protein.
Conclusion: Our findings suggest a functional mechanism that correlates SORL1 genotype with efficiency of receptor expression in the human brain.