A Gly98Val Mutation in the N-Myc Downstream Regulated Gene 1 (NDRG1) in Alaskan Malamutes with Polyneuropathy
| Autor: | G. Diane Shelton, Katie M. Minor, Lars Moe, Camilla S. Bruun, James R. Mickelson, Pall S. Leifsson, Inge Bjerkås, Jennie Ohlsson, Cecilia Rohdin, Rebecca Edlund, Kristine B. Jensen, Sigitas Cizinauskas, Hanne Gredal, Merete Fredholm, Cord Drögemüller, Hannes Lohi, Karin Hultin Jäderlund, Øyvind Stigen, Mette Berendt, Eva H. Spodsberg, Arild Espenes, Susanna Cirera |
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| Přispěvatelé: | Departments of Faculty of Veterinary Medicine, Research Programs Unit, Research Programme of Molecular Medicine, Veterinary Biosciences, Veterinary Genetics |
| Rok vydání: | 2013 |
| Předmět: |
Male
Candidate gene HEREDITARY MOTOR Alaskan malamute Cell Cycle Proteins medicine.disease_cause Exon 0302 clinical medicine Neurobiology of Disease and Regeneration Genotype Dog Diseases BRAIN Small Animals MARIE-TOOTH DISEASE Animal Management media_common Genetics 0303 health sciences Mutation education.field_of_study Multidisciplinary 630 Agriculture GYPSIES Intracellular Signaling Peptides and Proteins 3. Good health 590 Animals (Zoology) Medicine Female Polyneuropathy Veterinary Pathology Research Article Veterinary Medicine Animal Types Science education Population SENSORY NEUROPATHY-LOM Biology Veterinary Neurology Polyneuropathies 03 medical and health sciences Dogs Genetic Mutation medicine Animals media_common.cataloged_instance 030304 developmental biology Point mutation Human Genetics medicine.disease DEMYELINATING NEUROPATHY Genetics of Disease Immunology 1182 Biochemistry cell and molecular biology Veterinary Science 3111 Biomedicine Gene Function Animal Genetics 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | PLoS ONE, Vol 8, Iss 2, p e54547 (2013) Bruun, C V S, Jäderlund, K H, Berendt, M, Jensen, K B, Spodsberg, E-M H, Gredal, H B, Shelton, G D, Mickelson, J R, Minor, K M, Lohi, H, Bjerkås, I, Stigen, Ø, Espenes, A, Rohdin, C, Edlund, R, Ohlsson, J, Cizinauskas, S, Leifsson, P S, Drögemüller, C, Moe, L, Cirera Salicio, S & Fredholm, M 2013, ' A Gly98Val mutation in the N-myc downstream regulated gene 1 ( NDRG1 ) in Alaskan Malamutes with polyneuropathy ', PLOS one, vol. 8, no. 2, e54547, pp. 1-7 . https://doi.org/10.1371/journal.pone.0054547 PLoS ONE 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 PLoS ONE; Vol 8 |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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