Analysis of the c-FOS gene on chromosome 14 and the promoter of the amyloid precursor protein gene in familial alzheimer's disease

The c-FOS gene product, a putative transacting transcriptional regulator of the amyloid precursor protein (APP) gene, is a candidate locus for the familial Alzheimer's disease (FAD) mutation on chromosome 14 (FAD₁₄). In light of this functional relationship, we investigated the nucleotide sequence and segregation of c-FOS and the nucleotide sequence of the 5′ APP promoter. Single-stranded conformational polymorphisms (SSCPs) in the c-FOS gene revealed that c-FOS closely cosegregates with the FAD₁₄ gene but does not show allelic association with FAD. A conservative third-position T→C mutation was demonstrated in exon 2 (codon 84) of c-FOS, and a C→G substitution was detected at -209 bp in the 5′ promoter of APP. Neither were unique to FAD and are unlikely to be pathogenic or secondary modifiers of the FAD phenotype. We conclude that the c-FOS open reading frame is probably not the site of the FAD₁₄ locus, but we cannot exclude the existence of modifier loci on chromosome 21.