Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene

Abstract

Genetic mutations in the tau gene on chromosome 17 are known to cause frontotemporal dementias. We have identified a novel silent mutation (S305S) in the tau 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 tau 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.

Retarded Axonal Transport of R406W Mutant Tau in Transgenic Mice with a Neurodegenerative Tauopathy

“…For example, intronic and some exonic tau gene mutations affect alternative splicing of exon 10 and consequently change the relative proportion of tau isoforms with four or three microtubule (MT) binding repeats (Hong et al, 1998;Hutton et al, 1998;D'Souza et al, 1999;Delisle et al, 1999;Grover et al, 1999;Hasegawa et al, 1999;Varani et al, 1999;Yasuda et al, 1999Yasuda et al, , 2000Spillantini et al, 2000;Stanford et al, 2000). Other exonic tau gene mutations (e.g., P301L, R406W) impair the ability of tau to bind to and stabilize MTs as well as to promote the assembly of MTs (Hasegawa et al, 1998;Hong et al, 1998).…”

Regulation of Alternative Splicing of Human Tau Exon 10 by Phosphorylation of Splicing Factors

“…Most missense mutations act at the protein level and reduce the ability of tau to interact with microtubules (Hasegawa et al, 1998). Intronic mutations and the exonic mutations N279K, L284L, N296N, S305N, and S305S affect pre-mRNA processing and lead to an increase of exon 10 usage by changing either the 5Ј splice site composition or exonic elements in exon 10 (Clark et al, 1998;D'Souza et al, 1999;Hasegawa et al, 1999;Hutton et al, 1998;Spillantini et al, , 2000bStanford et al, 2000;Varani et al, 1999). As a result, the approximately equal ratio of 4R and 3R isoforms is shifted in favor of 4R tau.…”

From Protein Tangles to Genetic Variants: The Central Role of Tau in Neurodegenerative Disease

“…Like most alternatively spliced exons, exon 10 contains a weak 5' splice site, leading to a weak interaction with the U1 snRNP. This site is strengthened by the coding region mutations S305N/S and the intronic mutation +3, which results in increased exon 10 splicing (Hutton et al, 1998;Spillantini et al, 1998;Stanford et al, 2000). Notably, a large part of exon 10 is directly involved in splicing regulation, as it harbours several exonic splicing enhancers and a silencer.…”