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.

Juvenile‐onset polyneuropathy in American Staffordshire Terriers

“…A similar age was reported for Dalmatian, Pyrenean Mountain Dog, and Greyhound in which onset of clinical signs occurs during the first year of life . In the Alaskan Malamute, clinical signs occurred between 3 and 19 months of age . Finally, in the Leonberger, clinical signs occurred between 1 and 3 years of age in 70% of the animals examined .…”

“…In the other breeds, nonsyndromic forms lead to a disease similar to Charcot‐Marie‐Tooth (CMT) disease in humans, with axonal degeneration being a dominant finding . Mutations have been found for the Alaskan Malamute and Greyhound ( NDRG1 gene), and for the Leonberger ( ARHGEF10 and GJA9 genes), which allows for genetic screening …”

Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D

“…In addition, a 10 bp deletion leading to a frameshift (p.R361SerfsX60) and a single-nucleotide variant mutation (causing aa change p.G98V) have been described in both inbred Greyhound and Alaskan Malamute pedigrees with polyneuropathy. 23,24 AR peripheral neuropathies are relatively rare, but can be clinically more severe than autosomal-dominant forms of CMT. Clinically, HMSN-Lom/CMT4D presents with muscle weakness and wasting, tendon areflexia, skeletal and foot deformities, and sensory loss affecting all modalities.…”

CMT4D (NDRG1 mutation): genotype–phenotype correlations

“…The optical microscopic examinations of peripheral nerves from these dogs revealed a moderate to marked nerve fiber loss resulting from chronic axonal degeneration. No ultrastructural study has been realized (Bruun et al, 2013).…”