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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

journal contribution
posted on 2023-06-07, 22:42 authored by Azlina Ahmad-Annuar, Paresh Shah, Majid HafezparastMajid Hafezparast, Holger Hummerich, Abi S Witherden, Karen E Morrison, Pamela J Shaw, Janine Kirby, Thomas T Warner, Andrew Crosby, Christos Proukakis, Philip Wilkinson, Richard W Orrell, Lloyd Bradley, Joanne E Martin, Elizabeth M C Fisher
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.

History

Publication status

  • Published

Journal

Amyotrophic Lateral Sclerosis

ISSN

1748-2968

Publisher

Informa Healthcare

Issue

3

Volume

4

Page range

150-157

Department affiliated with

  • Neuroscience Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-02-06

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