Identification and confirmation of an exonic splicing enhancer variation in exon 5 of the Alzheimer disease associated PICALM gene

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory and cognitive impairment and is the leading cause of dementia in the elderly. A number of genome wide association studies and subsequent replication studies have been published recently on late onset AD (LOAD). These studies identified several new susceptibility genes including phosphatidylinositol-binding clathrin assembly protein (PICALM) on chromosome 11. The aim of our study was to examine the entire coding sequence of PICALM to determine if the association could be explained by any previously undetected sequence variation. Therefore, we sequenced 48 cases and 48 controls homozygous for the risk allele in the signal SNP rs3851179. We did not find any new variants; however, rs592297, a known coding synonymous SNP that is part of an exonic splice enhancer region in exon 5, is in strong linkage disequilibrium with rs3851179 and should be examined for functional significance in Alzheimer pathophysiology.