The first genetically characterized canine CMT model

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PLoS One. 2010 Jun 22;5(6):e11258.

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

with Polyneuropathy.

Drögemüller C, Becker D, Kessler B, Kemter E, Tetens J, Jurina K, Hultin

Jäderlund K, Flagstad A, Perloski M, Lindblad-Toh K, Matiasek K.

Institute of Genetics, Vetsuisse Faculty, University of Berne, Berne,

Switzerland.

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.