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No association with common Caucasian genotypes in exons 8, 13 and 14 of the human cytoplasmic dynein heavy chain gene (DNCHC1) and familial motor neuron disorders

No association with common Caucasian genotypes in exons 8, 13 and 14 of the human cytoplasmic dynein heavy chain gene (DNCHC1) and familial motor neuron disorders
No association with common Caucasian genotypes in exons 8, 13 and 14 of the human cytoplasmic dynein heavy chain gene (DNCHC1) and familial motor neuron disorders
We have shown in a mouse model of motor neuron disease, the legs?at?odd?angles (Loa) mutant, and that mutations in the cytoplasmic dynein heavy chain gene (Dnchc1) cause motor neuron degeneration. Mice exhibiting the Loa phenotype suffer progressive loss of locomotor function and homozygous animals have neuronal inclusion bodies that are positive for SOD1, CDK5, neurofilament and ubiquitin proteins. As this phenotype models some aspects of human motor neuron degeneration disorders, we think there is a reasonable likelihood that dynein may be a causative gene or susceptibility factor in human motor neuron disease. Therefore we have screened exons of this gene in a set of human patients with familial forms of disparate motor neuron degeneration diseases, affecting both upper and lower motor neurons: amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and hereditary spastic paraplegia. As part of this study, we have determined that DNCHC1 is a large gene of 78 exons spanning 86?kb genomic length. We have focused on the exons known to be mutated in Loa, and in a very similar mouse mutation, cramping 1 (Cra1); both mutations result in loss of anterior horn cells. The exons studied are highly conserved in a wide range of eukaryotes. We screened our patient samples by sequencing and although we detect single nucleotide polymorphisms, our results show these occur at the same frequency in our patient group as in control samples of unaffected individuals. Therefore we do not find any association between familial motor neuron disease and the genotypes presented here in the exons screened.
2167-8421
150-157
Ahmad‐Annuar, Azlina
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Shah, Paresh
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Hafezparast, Majid
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Hummerich, Holger
abe5dc3c-a563-4121-b5e2-57f527e0bbfc
Witherden, Abi S.
5fbebb1e-ae1b-4335-ad89-70119902282b
Morrison, Karen E.
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
Shaw, Pamela J.
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Kirby, Janine
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Warner, Thomas T.
677915c3-cb5f-4e76-a813-8b1d0781886b
Crosby, Andrew
705a4801-fc8f-45e0-850e-0a010e862133
Proukakis, Christos
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Wilkinson, Philip
0d1df0fb-7b33-4cb5-80c8-4e1e2f7a0f1b
Orrell, Richard W.
ef3e7a42-0965-4f2f-9ab0-1a645b00b61f
Bradley, Lloyd
5030ccda-acc7-435f-87d0-8e35874ab71d
Martin, Joanne E.
d671190a-4993-4cc3-9f07-ea51704198b4
Fisher, Elizabeth M.C.
297244d9-0d75-4e0e-a8cf-318e0bd1defd
Ahmad‐Annuar, Azlina
a7cba1cd-0ed5-4330-8b7f-026a72916531
Shah, Paresh
5f50bed1-6828-47b7-9878-32754a48806e
Hafezparast, Majid
835681d6-a6b9-4af7-9d9c-40a443381df6
Hummerich, Holger
abe5dc3c-a563-4121-b5e2-57f527e0bbfc
Witherden, Abi S.
5fbebb1e-ae1b-4335-ad89-70119902282b
Morrison, Karen E.
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
Shaw, Pamela J.
3d0a5c6f-9610-45be-a0bc-5b6888003028
Kirby, Janine
59b4a438-0185-46a5-a76c-9f96b0ea3fe2
Warner, Thomas T.
677915c3-cb5f-4e76-a813-8b1d0781886b
Crosby, Andrew
705a4801-fc8f-45e0-850e-0a010e862133
Proukakis, Christos
61752958-f365-4f1b-8491-864d6a1cb7fb
Wilkinson, Philip
0d1df0fb-7b33-4cb5-80c8-4e1e2f7a0f1b
Orrell, Richard W.
ef3e7a42-0965-4f2f-9ab0-1a645b00b61f
Bradley, Lloyd
5030ccda-acc7-435f-87d0-8e35874ab71d
Martin, Joanne E.
d671190a-4993-4cc3-9f07-ea51704198b4
Fisher, Elizabeth M.C.
297244d9-0d75-4e0e-a8cf-318e0bd1defd

Ahmad‐Annuar, Azlina, Shah, Paresh, Hafezparast, Majid, Hummerich, Holger, Witherden, Abi S., Morrison, Karen E., Shaw, Pamela J., Kirby, Janine, Warner, Thomas T., Crosby, Andrew, Proukakis, Christos, Wilkinson, Philip, Orrell, Richard W., Bradley, Lloyd, Martin, Joanne E. and Fisher, Elizabeth M.C. (2003) No association with common Caucasian genotypes in exons 8, 13 and 14 of the human cytoplasmic dynein heavy chain gene (DNCHC1) and familial motor neuron disorders. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 4 (3), 150-157. (doi:10.1080/14660820310011737).

Record type: Article

Abstract

We have shown in a mouse model of motor neuron disease, the legs?at?odd?angles (Loa) mutant, and that mutations in the cytoplasmic dynein heavy chain gene (Dnchc1) cause motor neuron degeneration. Mice exhibiting the Loa phenotype suffer progressive loss of locomotor function and homozygous animals have neuronal inclusion bodies that are positive for SOD1, CDK5, neurofilament and ubiquitin proteins. As this phenotype models some aspects of human motor neuron degeneration disorders, we think there is a reasonable likelihood that dynein may be a causative gene or susceptibility factor in human motor neuron disease. Therefore we have screened exons of this gene in a set of human patients with familial forms of disparate motor neuron degeneration diseases, affecting both upper and lower motor neurons: amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and hereditary spastic paraplegia. As part of this study, we have determined that DNCHC1 is a large gene of 78 exons spanning 86?kb genomic length. We have focused on the exons known to be mutated in Loa, and in a very similar mouse mutation, cramping 1 (Cra1); both mutations result in loss of anterior horn cells. The exons studied are highly conserved in a wide range of eukaryotes. We screened our patient samples by sequencing and although we detect single nucleotide polymorphisms, our results show these occur at the same frequency in our patient group as in control samples of unaffected individuals. Therefore we do not find any association between familial motor neuron disease and the genotypes presented here in the exons screened.

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More information

Accepted/In Press date: 12 May 2003
Published date: 2003
Organisations: Medical Education

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Local EPrints ID: 398842
URI: http://eprints.soton.ac.uk/id/eprint/398842
ISSN: 2167-8421
PURE UUID: d58652a4-2f54-471f-b3c0-fae48020d7c6
ORCID for Karen E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 02 Aug 2016 12:43
Last modified: 15 Mar 2024 01:43

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Contributors

Author: Azlina Ahmad‐Annuar
Author: Paresh Shah
Author: Majid Hafezparast
Author: Holger Hummerich
Author: Abi S. Witherden
Author: Karen E. Morrison ORCID iD
Author: Pamela J. Shaw
Author: Janine Kirby
Author: Thomas T. Warner
Author: Andrew Crosby
Author: Christos Proukakis
Author: Philip Wilkinson
Author: Richard W. Orrell
Author: Lloyd Bradley
Author: Joanne E. Martin
Author: Elizabeth M.C. Fisher

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