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

Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis
Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis
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.
1364-6745
217-225
Kirby, Janine
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Goodall, Emily F.
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Smith, William
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Highley, J. Robin
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Masanzu, Rudo
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Hartley, Judith A.
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Hibberd, Rachel
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Hollinger, Hannah C.
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Wharton, Stephen B.
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Morrison, Karen E.
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Ince, Paul G.
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McDermott, Christopher J.
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Shaw, Pamela J.
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Kirby, Janine
59b4a438-0185-46a5-a76c-9f96b0ea3fe2
Goodall, Emily F.
b1af5241-f788-44b5-966c-510db4ca24ef
Smith, William
5f6533e7-5ab8-4243-a09f-f63835bde614
Highley, J. Robin
c1f5dcc3-c83d-4e2e-9418-3979ff6b26d5
Masanzu, Rudo
81227b26-a13f-4c9c-ad96-be4260cdf1f2
Hartley, Judith A.
f8056065-0539-45c4-b1b3-1aa4b6f6ccac
Hibberd, Rachel
bbccf66d-9517-4917-a52d-2c36dfb55336
Hollinger, Hannah C.
c2766bf9-c0f2-4621-898a-ad452cbb5318
Wharton, Stephen B.
dc1ee8f7-ec50-4cb2-983c-4156a50a2005
Morrison, Karen E.
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Ince, Paul G.
c1b8f33a-238f-46ae-8edc-da2594c53e48
McDermott, Christopher J.
107ae1fb-878d-4197-a620-ee4fbb66f41d
Shaw, Pamela J.
3d0a5c6f-9610-45be-a0bc-5b6888003028

Kirby, Janine, Goodall, Emily F., Smith, William, Highley, J. Robin, Masanzu, Rudo, Hartley, Judith A., Hibberd, Rachel, Hollinger, Hannah C., Wharton, Stephen B., Morrison, Karen E., Ince, Paul G., McDermott, Christopher J. and Shaw, Pamela J. (2010) Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis. Neurogenetics, 11 (2), 217-225. (doi:10.1007/s10048-009-0218-9).

Record type: Article

Abstract

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.

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More information

Accepted/In Press date: 20 August 2009
Published date: May 2010
Organisations: Medical Education

Identifiers

Local EPrints ID: 398769
URI: http://eprints.soton.ac.uk/id/eprint/398769
ISSN: 1364-6745
PURE UUID: 7302cc3e-029f-4d20-b363-3a943c19ab2f
ORCID for Karen E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 01 Aug 2016 14:10
Last modified: 10 Dec 2019 01:32

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Contributors

Author: Janine Kirby
Author: Emily F. Goodall
Author: William Smith
Author: J. Robin Highley
Author: Rudo Masanzu
Author: Judith A. Hartley
Author: Rachel Hibberd
Author: Hannah C. Hollinger
Author: Stephen B. Wharton
Author: Paul G. Ince
Author: Christopher J. McDermott
Author: Pamela J. Shaw

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