Background: Pathogenic mutations in the presenilin 1 (PS1) gene leading to early-onset Alzheimer disease have been described in various populations. The different mutations are not distributed randomly in the PS1 protein but are clustered in some PS1 exons.
Objective: To screen the PS1 gene in search of a potential mutation in a Spanish family with early-onset Alzheimer disease.
Methods: Single-stranded conformational polymorphism and heteroduplex analyses of all exons were used to search for a potential mutation. Subsequent sequencing of the DNA samples with an abnormal heteroduplex pattern was performed to identity the mutation in the sense strand and in the complementary strand.
Results: We found a novel mutation in exon 6 of the PS1 gene at a site that, so far, had not been described as a cluster of mutations. The mutation (an A to C change) causes a substitution of leucine for arginine at position 166 of the PS1 protein and is located adjacent to the transmembrane domain III, where few mutations have been found. In this family, the disease follows an autosomal inheritance pattern with early onset (range, 32-44 years).
Conclusion: A novel missense mutation (Leu166Arg) at an atypical site associated with early-onset Alzheimer disease has been identified in a Spanish family.