A Gly98Val mutation in the N-Myc downstream regulated gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy.

Bruun, Camilla S; Jäderlund, Karin H; Berendt, Mette; Jensen, Kristine B; Spodsberg, Eva H; Gredal, Hanne; Shelton, G Diane; Mickelson, James R; Minor, Katie M; Lohi, Hannes; Bjerkås, Inge; Stigen, Oyvind; Espenes, Arild; Rohdin, Cecilia; Edlund, Rebecca; Ohlsson, Jennie; Cizinauskas, Sigitas; Leifsson, Páll S; Drögemüller, Cord; Moe, Lars; ... (2013). A Gly98Val mutation in the N-Myc downstream regulated gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy. PLoS ONE, 8(2), e54547. Public Library of Science 10.1371/journal.pone.0054547

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > NeuroCenter
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

UniBE Contributor:

Drögemüller, Cord

Subjects:

500 Science > 590 Animals (Zoology)
600 Technology > 630 Agriculture

ISSN:

1932-6203

Publisher:

Public Library of Science

Language:

English

Submitter:

Susanne Portner

Date Deposited:

04 Jul 2014 15:26

Last Modified:

13 Feb 2015 08:10

Publisher DOI:

10.1371/journal.pone.0054547

PubMed ID:

23393557

BORIS DOI:

10.7892/boris.43910

URI:

https://boris.unibe.ch/id/eprint/43910

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