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Identification of New Presenilin Gene Mutations in Early-Onset Familial Alzheimer Disease
Andrea Tedde, PhD;
Benedetta Nacmias, PhD;
Monica Ciantelli, MD;
Paolo Forleo, MD;
Elena Cellini, PhD;
Silvia Bagnoli, PhD;
Carolina Piccini, MD;
Paolo Caffarra, MD;
Enrico Ghidoni, MD;
Marco Paganini, MD;
Laura Bracco, MD;
Sandro Sorbi, MD
Arch Neurol. 2003;60:1541-1544.
Background Mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes, and more rarely in  -amyloid precursor protein (APP), underlie the pathogenesis of most cases of familial Alzheimer disease (FAD).
Objective To screen the entire coding region of the PS1 and PS2 genes and exons 16 and 17 of the APP 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 se-quencing 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 PS1 mutations: Cys92Ser in exon 4 in 2 unrelated families and Leu174Met in exon 6 in the PS1 gene. We also found a fourth Italian family with the APP Val717Ile mutation.
Conclusions One novel PS2 mutation associated with highly penetrant but variable age at onset (35-85 years) and 2 novel PS1 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 APP genes was beneficial in characterizing gene function in FAD.
From the Department of Neurological and Psychiatric Sciences, University of Florence, Italy (Drs Tedde, Nacmias, Ciantelli, Forleo, Cellini, Bagnoli, Piccini, Paganini, Bracco, and Sorbi); Institute of Neurology, University of Parma, Italy (Dr Caffarra); and the Neurological Department, Santa Maria Nuova Hospital, Reggio Emilia, Italy (Dr Ghidoni).
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