Progressive supranuclear palsy pathology caused by a novel silent mutationin exon 10 of the tau gene - Expansion of the disease phenotype caused by tau gene mutations

Genetic mutations in the tan gene on chromosome 17 are known to cause front otemporal dementias. We have identified a novel silent mutation (S305S) in the ran gene in a subject without significant atrophy or cellular degenerat ion of the frontal and temporal cortices, Rather the cellular pathology was characteristic of progressive supranuclear palsy, with neurofibrillary tan gles concentrating within the subcortical regions of the basal ganglia, Two affected family members presented with symptoms of dementia and Later deve loped neurological deficits including abnormality of vertical gaze and extr apyramidal signs. The third presented with dystonia of the left arm and dys arthria, and later developed a supranuclear gaze palsy and falls, The mutat ion is located in exon 10 of the tart gene and forms part of a stem-loop st ructure at the 5' splice donor site. Although the mutation does not give ri se to an amino acid change in the tau protein, functional exon-trapping exp eriments show that it results in a significant 4.8-fold increase in the spl icing of exon 10, resulting in the presence of tau containing four microtub ule-binding repeats. This study provides direct molecular evidence for a fu nctional mutation that causes progressive supranuclear palsy pathology and demonstrates that mutations in the tau gene are pleiotropic.