High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands

Mutations in microtubule-associated protein tau recently have been identifi ed in familial cases of frontotemporal dementia (FTD). We report the freque ncy of tart mutations in a large population-based study of FTD carried out in the Netherlands from January 1994 to June 1998. Thirty-seven patients ha d greater than or equal to 1 first-degree relative with dementia. A mutatio n in the taut gene was found in 17.8% of the group of patients with FTD and in 43% of patients with FTD who also had a positive family history of FTD. Three distinct missense mutations (G272V, P301L, R406W accounted for 15.6% of the mutations. These three missense mutations, and a single amino acid deletion (Delta K280) that was detected in one patient, strongly reduce the ability of tau to promote microtubule assembly. We also found an intronic mutation at position +33 after exon 9, which is likely to affect the altern ative splicing of tau. Tau mutations are responsible for a large proportion of familial FTD cases; however, there are also families with FTD in which no mutations in tau have been found, which indicates locus and/or allelic h eterogeneity, The different tart mutations may result in disturbances in th e interactions of the protein tau with microtubules, resulting in hyperphos phorylation of tau protein, assembly into filaments, and subsequent cell de ath.