Abstract

BackgroundCharcot-Marie-Tooth (CMT) disease is the most common neuromuscular disorder in humans affecting 40 out of 100,000 individuals. In 2008, we described the clinical, electrophysiological and pathological findings of a demyelinating motor and sensory neuropathy in Miniature Schnauzer dogs, with a suspected autosomal recessive mode of inheritance based on pedigree analysis. The discovery of additional cases has followed this work and led to a genome-wide association mapping approach to search for the underlying genetic cause of the disease.MethodsFor genome wide association screening, genomic DNA samples from affected and unaffected dogs were genotyped using the Illumina CanineHD SNP genotyping array. SBF2 and its variant were sequenced using primers and PCRs. RNA was extracted from muscle of an unaffected and an affected dog and RT-PCR performed. Immunohistochemistry for myelin basic protein was performed on peripheral nerve section specimens.ResultsThe genome-wide association study gave an indicative signal on canine chromosome 21. Although the signal was not of genome-wide significance due to the small number of cases, the SBF2 (also known as MTMR13) gene within the region of shared case homozygosity was a strong positional candidate, as 22 genetic variants in the gene have been associated with demyelinating forms of Charcot-Marie-Tooth disease in humans. Sequencing of SBF2 in cases revealed a splice donor site genetic variant, resulting in cryptic splicing and predicted early termination of the protein based on RNA sequencing results.ConclusionsThis study reports the first genetic variant in Miniature Schnauzer dogs responsible for the occurrence of a demyelinating peripheral neuropathy with abnormally folded myelin. This discovery establishes a genotype/phenotype correlation in affected Miniature Schnauzers that can be used for the diagnosis of these dogs. It further supports the dog as a natural model of a human disease; in this instance, Charcot-Marie-Tooth disease. It opens avenues to search the biological mechanisms responsible for the disease and to test new therapies in a non-rodent large animal model. In particular, recent gene editing methods that led to the restoration of dystrophin expression in a canine model of muscular dystrophy could be applied to other canine models such as this before translation to humans.

Highlights

  • Charcot-Marie-Tooth (CMT) disease is the most common neuromuscular disorder of the human population, affecting 40 out of 100,000 individuals in Europe and the United States (Skre, 1974; Pareyson & Marchesi, 2009; Reilly, Murphy & Laura, 2011) and more than 2.6 million people worldwide (Emery, 1991)

  • After exclusion of variants in the PMP22 and P0 myelin genes by direct sequencing, the aim of this study was to demonstrate that the demyelinating hereditary motor and sensory neuropathy in Miniature Schnauzer dogs was genetic in origin by conducting a genome-wide association study (GWAS) and resequencing of candidate genes

  • Our findings led us to suspect that variants of genes coding for: (i) myelin proteins; (ii) intracellular Schwann cell proteins involved in the synthesis, transport and degradation of myelin proteins including the myotubularin-related (MTMR) proteins; and (iii) regulating myelin gene transcription proteins, might be responsible for the disease (Previtali, Quattrini & Bolino, 2007; Suter & Scherer, 2003)

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Summary

Introduction

Charcot-Marie-Tooth (CMT) disease is the most common neuromuscular disorder of the human population, affecting 40 out of 100,000 individuals in Europe and the United States (Skre, 1974; Pareyson & Marchesi, 2009; Reilly, Murphy & Laura, 2011) and more than 2.6 million people worldwide (Emery, 1991). This study reports the first genetic variant in Miniature Schnauzer dogs responsible for the occurrence of a demyelinating peripheral neuropathy with abnormally folded myelin This discovery establishes a genotype/phenotype correlation in affected Miniature Schnauzers that can be used for the diagnosis of these dogs. Charcot-Marie-Tooth type 4B2 demyelinating neuropathy in miniature Schnauzer dogs caused by a novel splicing SBF2 (MTMR13) genetic variant: a new spontaneous clinical model.

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