A Deletion in the N-Myc Downstream Regulated Gene 1 (NDRG1) Gene in Greyhounds with Polyneuropathy

Abstract

The polyneuropathy of juvenile Greyhound show dogs shows clinical similarities to the genetically heterogeneous Charcot-Marie-Tooth (CMT) disease in humans. The pedigrees containing affected dogs suggest monogenic autosomal recessive inheritance and all affected dogs trace back to a single male. Here, we studied the neuropathology of this disease and identified a candidate causative mutation. Peripheral nerve biopsies from affected dogs were examined using semi-thin histology, nerve fibre teasing and electron microscopy. A severe chronic progressive mixed polyneuropathy was observed. Seven affected and 17 related control dogs were genotyped on the 50k canine SNP chip. This allowed us to localize the causative mutation to a 19.5 Mb interval on chromosome 13 by homozygosity mapping. The NDRG1 gene is located within this interval and NDRG1 mutations have been shown to cause hereditary motor and sensory neuropathy-Lom in humans (CMT4D). Therefore, we considered NDRG1 a positional and functional candidate gene and performed mutation analysis in affected and control Greyhounds. A 10 bp deletion in canine NDRG1 exon 15 (c.1080_1089delTCGCCTGGAC) was perfectly associated with the polyneuropathy phenotype of Greyhound show dogs. The deletion causes a frame shift (p.Arg361SerfsX60) which alters several amino acids before a stop codon is encountered. A reduced level of NDRG1 transcript could be detected by RT-PCR. Western blot analysis demonstrated an absence of NDRG1 protein in peripheral nerve biopsy of an affected Greyhound. We thus have identified a candidate causative mutation for polyneuropathy in Greyhounds and identified the first genetically characterized canine CMT model which offers an opportunity to gain further insights into the pathobiology and therapy of human NDRG1 associated CMT disease. Selection against this mutation can now be used to eliminate polyneuropathy from Greyhound show dogs.

Detection of <i>Nesopora caninum</i>-Specific DNA from Cerebrospinal Fluid by Polymerase Chain Reaction in a Dog with Confirmed Neosporosis

“…Meanwhile, it was reported that some juvenile Greyhound show dogs exhibited clinical signs of polyneuropathy, similar to that observed in neosporosis. Affected dogs also exhibited exercise intolerance and walking difficulties such as high stepping gait and 'bunnyhopping', but postural reactions seemed unaffected in the early stages of the disease [5]. These clinical signs were different from those observed in the dog in our case report.…”

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.…”

Pathological Features of Polyneuropathy in Three Dogs

“…Recently, Drögemüller et al [12] identified a deletion in the N-myc downstream regulated gene 1 (NDRG1) gene in greyhound polyneuropathy. It was recognized as the first genetically characterized canine model of human CMT disease, as the NDRG1 mutation had been identified in human CMT disease type 4D.…”