Recent origin and spread of a common Welsh MAPT splice mutation causing frontotemporal lobar degeneration.

摘要

IVS10+16C>T is the most prevalent mutation in the microtubule-associated protein tau gene (MAPT) causing frontotemporal lobar degeneration (FTLD) in populations of British descent. A highly conserved 17q21 haplotype was identified in IVS10+16C>T chromosomes from North Wales, Greater Manchester and the London areas of the UK, Australia, and the USA, suggesting the occurrence of a common founder effect. To test this hypothesis, the age of the mutation was estimated by parametric and Bayesian analysis of linkage disequilibrium's decay over generations, and the results were compared with historical and geographical data on FTLD families. The inferred age (23 generations; 95% confidence interval, 9-74 generations) dates the most recent common ancestor of IVS10+16C>T chromosomes before Welsh people started emigrating to the USA and Australia, where they introduced the mutation. The identification of a cohort of FTLD families with a homogeneous genetic background within and around the MAPT locus will further the investigation of the different clinical and pathological presentations of patients with identical MAPT mutations.