The human FE65 gene: genomic structure and an intronic biallelic polymorphism associated with sporadic dementia of the Alzheimer type.

The FE65 protein binds to the intracellular domain of the beta-amyloid precursor protein (betaPP) and may modulate the internalization of betaPP. This gene is highly expressed in regions of the brain specifically affected in dementia of the Alzheimer type (DAT). As a prelude to further investigations of the role of FE65 in the metabolism of betaPP and in the pathogenesis of DAT, we have determined the entire genomic structure and sequence of human FE65 and have discovered several polymorphisms in this gene. Human FE65 contains 14 exons ranging in size from 6 to 735 bp. All splice sites conform to consensus sequences except for the donor site of intron 10. The 5' end of FE65 mRNA was identified by rapid amplification of the cDNA 5' end and is 31 bp longer than the previously published cDNA sequence. The 5'-flanking region of this gene is TATA-less and is very GC-rich with at least five putative Sp1 binding sites. In comparison to the genomic rat FE65 sequence, the human FE65 5'-untranslated region is 134 bp longer and has an extra exon (exon 1, 86 bp). To identify mutations/polymorphisms of the coding regions of this gene, we performed blinded analysis of 457 Caucasian case-control samples from a large epidemiological study of sporadic DAT. Screening was conducted by single-strand conformation polymorphism. Four minor variants were found within the coding region, with frequencies between 0.002 and 0.015; two of the four result in amino acid substitutions. The more informative biallelic polymorphism (a trinucleotide deletion and a single base substitution) was found within intron 13 (84 bp), which interrupts two exons encoding the betaPP binding site. The frequency of the minor allele in this intron was 0.097 in DAT cases and 0.161 in controls (chi2=7.78, P=0.0054). Having at least one copy of the minor allele was associated with a decreased risk for DAT (chi2=9.20, P<0.005, odds ratio=0.49, 95% CI 0.31-0.77). Multivariate analysis showed that this association was independent of the APOE genotype. These results suggest that either FE65 itself or a closely linked gene influences the pathogenesis of sporadic DAT. The interaction of FE65 with betaPP and the association of a FE65 polymorphism with DAT lend credence to the hypothesis that the metabolism of betaPP is central to the pathogenesis of common sporadic forms of DAT.