Peer-reviewed veterinary case report
Gly98Val gene mutation linked to nerve disease in Alaskan Malamutes
By Bruun, Camilla S et al.·Published in PloS one·2013·Department of Veterinary Clinical and Animal Sciences·View original on PubMed →
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Original publication title: A Gly98Val mutation in the N-Myc downstream regulated gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy.
- Species:
- dog
Plain-English summary
A group of Alaskan Malamutes were found to have early-onset progressive polyneuropathy, a condition that affects their ability to walk and can lead to severe weakness. Symptoms included difficulty with movement, decreased reflexes, and muscle wasting. Researchers identified a specific genetic mutation (Gly98Val) in the NDRG1 gene that is likely responsible for this condition. By testing a larger group of dogs, they confirmed that affected dogs carried this mutation, while healthy dogs did not. This discovery could help breeders eliminate the disease from the breed by avoiding this genetic mutation in future breeding.
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Abstract
The first cases of early-onset progressive polyneuropathy appeared in the Alaskan Malamute population in Norway in the late 1970s. Affected dogs were of both sexes and were ambulatory paraparetic, progressing to non-ambulatory tetraparesis. On neurologic examination, affected dogs displayed predominantly laryngeal paresis, decreased postural reactions, decreased spinal reflexes and muscle atrophy. The disease was considered eradicated through breeding programmes but recently new cases have occurred in the Nordic countries and the USA. The N-myc downstream-regulated gene (NDRG1) is implicated in neuropathies with comparable symptoms or clinical signs both in humans and in Greyhound dogs. This gene was therefore considered a candidate gene for the polyneuropathy in Alaskan Malamutes. The coding sequence of the NDRG1 gene derived from one healthy and one affected Alaskan Malamute revealed a non-synonymous G>T mutation in exon 4 in the affected dog that causes a Gly98Val amino acid substitution. This substitution was categorized to be "probably damaging" to the protein function by PolyPhen2 (score: 1.000). Subsequently, 102 Alaskan Malamutes from the Nordic countries and the USA known to be either affected (n = 22), obligate carriers (n = 7) or healthy (n = 73) were genotyped for the SNP using TaqMan. All affected dogs had the T/T genotype, the obligate carriers had the G/T genotype and the healthy dogs had the G/G genotype except for 13 who had the G/T genotype. A protein alignment showed that residue 98 is conserved in mammals and also that the entire NDRG1 protein is highly conserved (94.7%) in mammals. We conclude that the G>T substitution is most likely the mutation that causes polyneuropathy in Alaskan Malamutes. Our characterization of a novel candidate causative mutation for polyneuropathy offers a new canine model that can provide further insight into pathobiology and therapy of human polyneuropathy. Furthermore, selection against this mutation can now be used to eliminate the disease in Alaskan Malamutes.
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Search related cases →Original publication on PubMed: https://pubmed.ncbi.nlm.nih.gov/23393557/