A novel mutation in the predicted TM2 domain of the presenilin 2 gene in a Spanish patient with late-onset Alzheimer's disease.

Mutations in the presenilin-2 (PS-2) gene are less frequent than mutations in the PS-1 gene. All mutations described in the PS-1 gene were found in early-onset Alzheimer's disease (AD) patients. At present, there are two missense mutations described for the PS-2 gene in some AD pedigrees. We have therefore analyzed transmembrane 2 (TM2) and TM5 domains of the PS-2 gene in AD patients and in a group of age-matched healthy controls. In a patient who was clinically diagnosed as having late-onset AD, we found a novel missense mutation consisting of a G->A substitution on exon 5 of the PS-2 gene, which results in a Val to Ile substitution at codon 148 within the predicted TM2 domain of the PS-2 protein. This is the third mutation described in the PS-2 gene and the first presenilin mutation detected in a Spanish AD patient. Both, the N141I mutation and the V148I mutation described here are located within the predicted TM2 domain and both were found in late-onset AD kindreds, whereas the mutation within the predicted TM5 domain was found in an early-onset AD pedigree. Carriers of mutations within TM2 of PS-1 have a mean age at onset of 40 years, while the other mutations in PS-1 occur in families with a mean age at onset of 47 years. In summary, we report here the first mutation in a presenilin gene in a Spanish AD case, which is the third mutation detected for the PS-2 gene.