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

被引:208
作者
Stanford, PM
Halliday, GM
Brooks, WS
Kwok, JBJ
Storey, CE
Creasey, H
Morris, JGL
Fulham, MJ
Schofield, PR
机构
[1] Garvan Inst Med Res, Sydney, NSW 2010, Australia
[2] Prince Wales Med Res Inst, Randwick, NSW, Australia
[3] Univ Sydney, Ctr Educ & Res Ageing, Concord Hosp, Concord, Australia
[4] Royal N Shore Hosp, Dept Neurol, St Leonards, NSW 2065, Australia
[5] Westmead Hosp, Dept Neurol, Westmead, NSW 2145, Australia
[6] Royal Prince Alfred Hosp, Dept PET & Nucl Med, Camperdown, NSW 2050, Australia
关键词
progressive supranuclear palsy; frontotemporal dementia with Parkinsonism; corticobasal degeneration; tau; mutations;
D O I
10.1093/brain/123.5.880
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Genetic mutations in the tan gene on chromosome 17 are known to cause frontotemporal dementias. We have identified a novel silent mutation (S305S) in the ran gene in a subject without significant atrophy or cellular degeneration of the frontal and temporal cortices, Rather the cellular pathology was characteristic of progressive supranuclear palsy, with neurofibrillary tangles concentrating within the subcortical regions of the basal ganglia, Two affected family members presented with symptoms of dementia and Later developed neurological deficits including abnormality of vertical gaze and extrapyramidal signs. The third presented with dystonia of the left arm and dysarthria, and later developed a supranuclear gaze palsy and falls, The mutation is located in exon 10 of the tart gene and forms part of a stem-loop structure at the 5' splice donor site. Although the mutation does not give rise to an amino acid change in the tau protein, functional exon-trapping experiments show that it results in a significant 4.8-fold increase in the splicing of exon 10, resulting in the presence of tau containing four microtubule-binding repeats. This study provides direct molecular evidence for a functional mutation that causes progressive supranuclear palsy pathology and demonstrates that mutations in the tau gene are pleiotropic.
引用
收藏
页码:880 / 893
页数:14
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