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Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

Kirby, J., Goodall, E.F., Smith, W., Highley, J.R., Masanzu, R., Hartley, J.A., Hibberd, R., Hollinger, H.C., Wharton, S.B., Morrison, K.E., Ince, P.G., McDermott, C.J. and Shaw, P.J. (2010) Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis. Neurogenetics, 11 (2). pp. 217-225. ISSN 1364-6745

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The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the transactive response-DNA binding protein (TARDBP) gene, encoding TDP-43. All but one are in exon 6, which encodes the glycine-rich domain. The aim of this study was to determine the frequency of TARDBP mutations in a large cohort of motor neurone disease patients from Northern England (42 non-superoxide dismutase 1 (SOD1) familial ALS (FALS), nine ALS-frontotemporal dementia, 474 sporadic ALS (SALS), 45 progressive muscular atrophy cases). We identified four mutations, two of which were novel, in two familial (FALS) and two sporadic (SALS) cases, giving a frequency of TARDBP mutations in non-SOD1 FALS of 5% and SALS of 0.4%. Analysis of clinical data identified that patients had typical ALS, with limb or bulbar onset, and showed considerable variation in age of onset and rapidity of disease course. However, all cases had an absence of clinically overt cognitive dysfunction.

Item Type: Article
Copyright, Publisher and Additional Information: © 2010 Springer. This is an author produced version of a paper subsequently published in Neurogenetics. Uploaded in accordance with the publisher's self-archiving policy.
Keywords: MND; ALS; TDP-43; TARDBP; Mutation
Institution: The University of Sheffield
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield)
Depositing User: Miss Anthea Tucker
Date Deposited: 28 May 2010 09:37
Last Modified: 08 Feb 2013 17:00
Published Version: http://dx.doi.org/10.1007/s10048-009-0218-9
Status: Published
Publisher: Springer Verlag
Refereed: Yes
Identification Number: 10.1007/s10048-009-0218-9
URI: http://eprints.whiterose.ac.uk/id/eprint/10847

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