Identification of new presenilin gene mutations in early-onset familial Alzheimer disease

Background: Mutations in the presenilin I (PSI) and presenilin 2 (PS2) genes, and more rarely in P-amyloid precursor protein (PAPP), underlie the pathogenesis of most cases of familial Alzheimer disease (FAD). Objective: To screen the entire coding region of the PSI and PS2 genes and exons 16 and 17 of the PAPP to find pathogenetic mutations in FAD. Patients: Patients with FAD were consecutively enrolled from among the outpatients from the neurology departments at the Universities of Florence and Parma and the Santa Maria Nuova Hospital in Reggio Emilia, Italy. Design and Methods: Polymerase chain reaction-single-strand conformation polymorphism and DNA sequencing were used to investigate the affected members of families with FAD. Results: We identified a family carrying a novel Ser130Leu mutation in the PS2 gene. Moreover, we found 2 novel PSI mutations: Cys92Ser in exon 4 in 2 unrelated families and Leu174Met in exon 6 in the PSI gene. We also found a fourth Italian family with the PAPP Val717Ile mutation. Conclusions: One novel PS2 mutation associated with highly penetrant but variable age at onset (35-85 years) and 2 novel PSI missense mutations associated with early-onset Alzheimer disease at age 49 to 54 years have been identified in Italian families. Screening for new mutations in presenilin and PAPP genes was beneficial in characterizing gene function in FAD.