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P3‐277: TAU V363I mutation: Pathogenic or not?

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

10.1016/j.jalz.2008.05.1845

1552-5279

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

Alzheimer's disease research and treatments

Mutations in TAU gene can cause neurodegenerative syndromes known as “tauopathies” such as Progressive supranuclear palsy, Corticobasal degeneration and Frontotemporal dementia (FTD). Mutations, generally highly penetrant, are of two types: 1) intronic disrupting splicing of tau and 2) missense altering protein function. Indeed, different mutations with multiple pathological mechanisms may explain the phenotypic heterogeneity. However, it remains uncertain yet whether a particular mutation is always associated to a specific phenotype. Objective of this study is to report the V363I mutation in exon 12 of TAU gene, in a proband clinically presenting with FTD and belonging to a three generations family. FTD diagnosis was performed on the basis of history and clinical evaluation, Lund-Manchester criteria and neuroimaging. TAU exons 1–13 were analyzed by automatic sequencing. The woman, aged 52, started to present with lack of critic and judgement, reduction of language, absence of insight, apathy, indifference in home and family management. Bulimia, disinhibition, wandering and incontinence occurred thereafter. In the late stage she became completely mute. She died at 61. TAU gene analysis showed the (G →A) transition of codon 363, that is not a common polymorphism, since it has not been found in 200 unrelated subjects. V363I was detected in 4 asymptomatic siblings: proband's mother, one out of the two sisters and her two children. Tau V363I has previously been identified in a familial case showing progressive nonfluent aphasia, in which the other mutated relatives (even older) presented with only moderate disturbances of language. Our case showed a clear picture of FTD but the other mutated first degree relatives did not manifest any symptoms. Demonstration of pathogenicity of the mutation is rather far and has to proceed through in vitro and animals models to evaluate the possible protein abnormal function.