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P3-220: PS1 polymorphism and a novel PS2 mutation in a patient with late-onset familial Alzheimer's disease

2008; Wiley; Volume: 4; Issue: 4S_Part_18 Linguagem: Inglês

10.1016/j.jalz.2008.05.1787

1552-5279

Maura Gallo, Carmine Tomaino, Livia Bernardi, Raffaele Maletta, Maria Anfossi, Sivana Geracitano, Franca Vasso, Gianfranco Puccio, Rosanna Colao, Francesca Frangipane, Maria Mirabelli, Nicoletta Smirne, Maria Gabriella Muraca, Ornella De Vito, Amalia C. Bruni,

Alzheimer's disease research and treatments

Mutations in one of the three known genes such as APP, encoding the Amyloid precursor protein (APP) and Presenilin (PS1 and PS2) account for approximately only 5% to 10% of all Alzheimer's Disease (AD) cases showing autosomal dominant familial form (FAD).Objective of this study is to report a novel PS2 missense mutation and the PS1 Glu318Gly polymorphism in a FAD late onset patient. Patient was diagnosed as affected by FAD. Family history reported that the father (deceased at age > 80 years) and two sisters (deceased at 74 and 83 years, respectively) were affected by a dementia clinically resembling that of the proband. In this family, proband presented a novel heterozygous transition (G→A) in the first position of the codon 139, which predicted a valine to methionine substitution in the PS2 gene. The absence of this substitution was verified in 100 FAD patients, and in 100 age-matched unrelated controls, indicating that it is not a common polymorphism. PS1 Glu318Gly polymorphism was also carried by proband. APOE genotype was 3/4. The Val139Met occurs in the boundary of second transmembrane domain of the protein, in which another pathogenic mutation (N141L) was described associated to early-onset FAD. and significantly increasing Aβ42 level, comparable with other PS2 pathogenic mutations. It could be reasonable, indeed, that the Val139Met mutation could act with a similar mechanism, although its pathogenicity remains to be definitively established. On the other hand, since the Valine 139 in PS2 is not conserved with respect to its homologue PS1 protein, this mutation could be considered not pathogenic. The pathogenic role of PS1 Glu318Gly polymorphism has been so far debated in the literature. Our study it is unable to get a conclusive response about its pathogenicity: we cannot exclude involvement of the polymorphism in causing the disease, in association (or not) with APOE genotype and PS2 mutation.