title: A Gly98Val mutation in the N-Myc downstream regulated gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy.
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.
authors: Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark. cvb@sund.ku.dk
authors: Camilla S
authors: CS
authors: Bruun
authors: Karin H
authors: KH
authors: Jäderlund
authors: Mette
authors: M
authors: Berendt
authors: Kristine B
authors: KB
authors: Jensen
authors: Eva H
authors: EH
authors: Spodsberg
authors: Hanne
authors: H
authors: Gredal
authors: G Diane
authors: GD
authors: Shelton
authors: James R
authors: JR
authors: Mickelson
authors: Katie M
authors: KM
authors: Minor
authors: Hannes
authors: H
authors: Lohi
authors: Inge
authors: I
authors: Bjerkås
authors: Oyvind
authors: O
authors: Stigen
authors: Arild
authors: A
authors: Espenes
authors: Cecilia
authors: C
authors: Rohdin
authors: Rebecca
authors: R
authors: Edlund
authors: Jennie
authors: J
authors: Ohlsson
authors: Sigitas
authors: S
authors: Cizinauskas
authors: Páll S
authors: PS
authors: Leifsson
authors: Cord
authors: C
authors: Drögemüller
authors: Lars
authors: L
authors: Moe
authors: Susanna
authors: S
authors: Cirera
authors: Merete
authors: M
authors: Fredholm
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation; D011115:Polyneuropathies / Q000235:genetics*; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein
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