OMIA 002120-9615 : Polyneuropathy, NDRG1-related in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 601455 (trait) , 605262 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2010

Species-specific description: The polyneuropathy of juvenile Greyhounds shows clinical similarities to the genetically heterogeneous Charcot-Marie-Tooth disease in humans.

Molecular basis: After genotyping 7 affected Grehounds and 17 normal related Greyhounds with the 50K dog SNP chip, Drögemüller et al. (2010) used homozygosity mapping to identify the candidate 19.5 Mb region on chromosome CFA13. By sequencing the most likely candidate gene in this region, they identified the causative mutation as a 10 bp deletion in exon 15 of the NDRG1 gene (c.1080_1089del10).

Bruun et al. (2013) investigated the same disorder in Alaskan Malumutes and reported a novel mutation in the same gene: "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." The causative variant in the Alaskan Malamute is c.293G>T.

Clinical features: In Greyhounds, this polyneuropathy becomes evident in juvenile dogs between the ages of three and nine months (Drögemüller et al., 2010). Early clinical features include exercise intolerance (e.g. shaking and collapse after exercise), abnormal gait (e.g. bunny hopping and high stepping), while ataxia, dysphonia and severe muscle atrophy were associated with later clinical features (Drögemüller et al., 2010). Neurological examination may reveal progressive lower motor neuron signs, including progressive ataxia and tetraparesis, delayed proprioceptive paw positioning, distal limb muscle atrophy, hyporeflexia, and inspiratory stridor (high pitched noise during inspiration) (Drögemüller et al., 2010).

[IT thanks DVM student Anna Johnston, who provided the basis of this contribution in April 2022.]

Pathology: In Greyhounds, a mild to marked decrease in the density of myelinated nerve fibres can be observed. A proportion of the remaining nerve fibres may show a “marked to severe loss of circularity due to para- and internodal crenation” and “outfolded myelin loops at paranodes” (Drögemüller et al., 2010). In approximately 10% of the large, myelinated fibres a mild to marked hyperplasia of axon-Schwann cell network can be seen (Drögemüller et al., 2010). Signs of chronic denervation may be present, including neurogenic atrophy present within some skeletal muscles, de-myelination of fibres within intramuscular nerve branches, as well as perimysial lipid accumulation (Drögemüller et al., 2010).

A study of affected Alaskan Malamutes found that these dogs demonstrated more than a 70% reduction in expression of the NDRG1 protein. This suggests that affected animals produce insufficient NDRG1 protein levels for the maintenance of the myelin of Schwann cells, thus resulting in this progressive degenerative polyneuropathy (Skedsmo et al., 2021).

[IT thanks DVM student Anna Johnston, who provided the basis of this contribution in April 2022.]

Prevalence: By genotyping archived samples, Jäderlund et al. (2017) showed that "historical and recent phenotypic polyneuropathy cases were carrying the same NDRG1-mutation [c.293G>T; p.Gly98Val]. The pedigree analysis showed that all affected Alaskan malamute cases with polyneuropathy could be traced back to one common ancestor of North American origin."

Breeds: Alaskan Malamute, Greyhound.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
NDRG1 N-myc downstream regulated 1 Canis lupus familiaris 13 NC_051817.1 (30105421..30048859) NDRG1 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
474 Greyhound Polyneuropathy NDRG1 deletion, small (<=20) Naturally occurring variant CanFam3.1 13 g.29691070_29691079del10 c.1080_1089del10 p.(R361Sfs*60) NM_001284434.1; NP_001271363.1 2010 20582309 Genomic position in CanFam3.1 provided by Robert Kuhn and Mateo Etcheveste.
73 Alaskan Malamute Polyneuropathy NDRG1 missense Naturally occurring variant CanFam3.1 13 g.29714606C>A c.293G>T p.(G98V) NM_001284434.1; NP_001271363.1 2013 23393557 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2022 Hultman, J., Jäderlund, K.H., Moe, L., Espenes, A., Skedsmo, F.S. :
Tongue atrophy as a neurological finding in hereditary polyneuropathy in Alaskan malamutes. J Vet Intern Med 36:672-678, 2022. Pubmed reference: 35019187. DOI: 10.1111/jvim.16351.
2021 Skedsmo, F.S., Espenes, A., Tranulis, M.A., Matiasek, K., Gunnes, G., Bjerkås, I., Moe, L., Røed, S.S., Berendt, M., Fredholm, M., Rohdin, C., Shelton, G.D., Bruheim, P., Stafsnes, M.H., Bartosova, Z., Hermansen, L.C., Stigen, Ø., Jäderlund, K.H. :
Impaired NDRG1 functions in Schwann cells cause demyelinating neuropathy in a dog model of Charcot-Marie-Tooth type 4D. Neuromuscul Disord 31:56-68, 2021. Pubmed reference: 33334662. DOI: 10.1016/j.nmd.2020.11.010.
2017 Jäderlund, K.H., Rohdin, C., Berendt, M., Stigen, Ø., Fredholm, M., Espenes, A., Bjerkås, I., Moe, L. :
Re-emergence of hereditary polyneuropathy in Scandinavian Alaskan malamute dogs-old enemy or new entity? A case series. Acta Vet Scand 59:26, 2017. Pubmed reference: 28464941. DOI: 10.1186/s13028-017-0295-y.
2013 Bruun, C.S., Jäderlund, K.H., Berendt, M., Jensen, K.B., Spodsberg, E.H., Gredal, H., Shelton, G.D., Mickelson, J.R., Minor, K.M., Lohi, H., Bjerkås, I., Stigen, O., Espenes, A., Rohdin, C., Edlund, R., Ohlsson, J., Cizinauskas, S., Leifsson, P.S., Drögemüller, C., Moe, L., Cirera, S., Fredholm, M. :
A Gly98Val mutation in the N-Myc Downstream Regulated Gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy. PLoS One 8:e54547, 2013. Pubmed reference: 23393557. DOI: 10.1371/journal.pone.0054547.
2012 Rentmeister, K., Bilzer, T., Petri, S., Schanen, G., Fehr, M., Distl, O., Tipold, A. :
Hereditary polyneuropathy in the Alaskan Malamute. Tierarztl Prax Ausg K Kleintiere Heimtiere 40:26-34, 2012. Pubmed reference: 22331326.
2010 Drögemüller, C., Becker, D., Kessler, B., Kemter, E., Tetens, J., Jurina, K., Jaderlund, KH., Flagstad, A., Perloski, M., Lindblad-Toh, K., Matiasek, K. :
A deletion in the N-myc downstream regulated gene 1 (NDRG1) gene in Greyhounds with polyneuropathy. PLoS One 5:e11258, 2010. Pubmed reference: 20582309. DOI: 10.1371/journal.pone.0011258.
2009 Wakshlag, JJ., de Lahunta, A. :
Hereditary encephalomyelopathy and polyneuropathy in an Alaskan husky. J Small Anim Pract 50:670-4, 2009. Pubmed reference: 19954445. DOI: 10.1111/j.1748-5827.2009.00857.x.
1997 Braund, K.G., Shores, A., Lowrie, C.T., Steinberg, H.S., Moore, M.P., Bagley, R.S., Steiss, J.E. :
Idiopathic polyneuropathy in Alaskan Malamutes Journal of Veterinary Internal Medicine 11:243-249, 1997. Pubmed reference: 9298480.

Edit History


  • Created by Frank Nicholas on 31 Aug 2017
  • Changed by Frank Nicholas on 31 Aug 2017
  • Changed by Imke Tammen2 on 11 Dec 2020
  • Changed by Imke Tammen2 on 14 Jan 2022
  • Changed by Imke Tammen2 on 23 May 2022