Journal Article

Segregation of a Missense Mutation in the Microtubule-Associated Protein Tau Gene with Familial Frontotemporal Dementia and Parkinsonism

Cécile Dumanchin, Agnès Camuzat, Dominique Campion, Patrice Verpillat, Didier Hannequin, Bruno Dubois, Pascale Saugier-Veber, Cosette Martin, Christiane Penet, Françoise Charbonnier, Yves Agid, Thierry Frebourg and Alexis Brice

in Human Molecular Genetics

Volume 7, issue 11, pages 1825-1829
Published in print October 1998 | ISSN: 0964-6906
Published online October 1998 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/7.11.1825
Segregation of a Missense Mutation in the Microtubule-Associated Protein Tau Gene with Familial Frontotemporal Dementia and Parkinsonism

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Frontotemporal dementia and parkinsonism (FTDP) is the second most common cause of neurodegenerative dementia after Alzheimer's disease. Recently, several kindreds with an autosomal dominant form of FTDP have been reported and in some families the pathological locus was mapped to a 2 cM interval on 17q21–22. The MAPT gene, located on 17q21 and coding for the human microtubule-associated protein tau, is a strong candidate gene, since tau-positive neuronal inclusions have been observed in brains from some FTDP patients. Direct sequencing of the MAPT exonic sequences in 21 French FTDP families revealed in six index cases the same missense mutation in exon 10 resulting in a Pro→Leu change at amino acid 301. Co-segregation of this mutation with the disease was demonstrated by restriction fragment analysis in two families for which several affected relatives were available. The Pro301Leu mutation was not observed in either 50 unrelated French controls or in 11 patients with sporadic frontotemporal dementia. This mutation, which occurs in the second microtubule-binding domain of the MAPT protein, is likely to have a drastic functional consequence. The observation of this mutation in several FTDP families might suggest that disruption of binding of MAPT protein to the microtubule is a key event in the pathogenesis of FTDP.

Journal Article.  2502 words.  Illustrated.

Subjects: Genetics and Genomics

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