Clinically-Silent Mutation in the Putative Iron-Responsive Element in Exon 17 of the β-Amyloid Precursor Protein Gene

Three missense mutations in exon 17 of the /3-amyloid precursor protein (APP) gene have been reported to cosegregate in families with early onset Alzheimerʼs disease (AD). All three mutations result in amino acid substitutions at codon 717 and may produce AD by altering the structure of the transmembrane domain of APP. Alternatively, the mutations may destabilize the stem of a putative iron-responsive element (IRE) in which they lie and confer pathogenicity by inactivating this negative regulatory element. We have detected a clinically-silent mutation in codon 716 that would also be expected to disrupt the putative IRE but results in no amino acid substitution. This result strongly suggests that the missense mutations at codon 717 produce AD by altering the amino acid sequence of APP rather than the IRE. Furthermore, the identification of a clinically-silent mutation among four point mutations that span only three nucleotides of exon 17 suggests that this region may be a mutational “hot” spot.