title: 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.
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Berne, Berne, Switzerland. Cord.Droegemueller@itz.unibe.ch
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
authors.forename: Doreen
authors.initials: D
authors.lastname: Becker
authors.forename: Barbara
authors.initials: B
authors.lastname: Kessler
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kemter
authors.forename: Jens
authors.initials: J
authors.lastname: Tetens
authors.forename: Konrad
authors.initials: K
authors.lastname: Jurina
authors.forename: Karin Hultin
authors.initials: KH
authors.lastname: Jäderlund
authors.forename: Annette
authors.initials: A
authors.lastname: Flagstad
authors.forename: Michele
authors.initials: M
authors.lastname: Perloski
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
authors.forename: Kaspar
authors.initials: K
authors.lastname: Matiasek
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D005260:Female; D017353:Gene Deletion; D006720:Homozygote; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D011115:Polyneuropathies / Q000235:genetics / Q000662:veterinary*; D020133:Reverse Transcriptase Polymerase Chain Reaction; 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