Different mutations at V363 MAPT codon are associated with atypical clinical phenotypes and show unusual structural and functional features.

Abstract

Microtubule-associated protein tau gene (MAPT) is one of the major genes linked to frontotemporal lobar degeneration, a group of neurodegenerative diseases clinically, pathologically, and genetically heterogeneous. In particular, MAPT mutations give rise to the subgroup of tauopathies. The pathogenetic mechanisms underlying the MAPT mutations so far described are the decreased ability of tau protein to promote microtubule polymerization (missense mutations) or the altered ratio of tau isoforms (splicing mutations), both leading to accumulation of hyperphosphorylated filamentous tau protein. Following a genetic screening of patients affected by frontotemporal lobar degeneration, we identified 2 MAPT mutations, V363I and V363A, leading to atypical clinical phenotypes, such as posterior cortical atrophy. We investigated in vitro features of the recombinant mutated tau isoforms and revealed unusual functional and structural characteristics such as an increased ability to promote microtubule polymerization and a tendency to form oligomeric instead of filamentous aggregates. Thus, we disclosed a greater than expected complexity of abnormal features of mutated tau isoforms. Overall our findings suggest a high probability that these mutations are pathogenic.

DOI: 10.1016/j.neurobiolaging.2013.08.004
050100150201520162017
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@article{Rossi2014DifferentMA, title={Different mutations at V363 MAPT codon are associated with atypical clinical phenotypes and show unusual structural and functional features.}, author={Giacomina Rossi and Antonio Bastone and Elena Piccoli and Michela Morbin and Giulia Mazzoleni and Valeria Fugnanesi and Marten Beeg and Elena del Favero and Laura Zapata Cant{\'u} and Simona Motta and Ettore Salsano and Davide Pareyson and A Erbetta and A E Elia and Francesca del Sorbo and Vincenzo Silani and Claudia Morelli and Mario Salmona and Fabrizio Tagliavini}, journal={Neurobiology of aging}, year={2014}, volume={35 2}, pages={408-17} }