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An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs.

  • Ekenstedt KJ Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America.
  • Becker D Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
  • Minor KM Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America.
  • Shelton GD Comparative Neuromuscular Laboratory, Department of Pathology, University of California San Diego, La Jolla, California, United States of America.
  • Patterson EE Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America.
  • Bley T Small Animal Clinic, Neruology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
  • Oevermann A Neurocenter, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
  • Bilzer T Institute of Neuropathology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
  • Leeb T Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
  • Drögemüller C Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
  • Mickelson JR Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America.
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  • 2014-10-03
Published in:
  • PLoS genetics. - 2014
Age Factors
Age of Onset
Animals
Case-Control Studies
Dog Diseases
Dogs
Female
Gene Deletion
Genome-Wide Association Study
Homozygote
Male
Mutation
Polymorphism, Single Nucleotide
Polyneuropathies
RNA Splice Sites
Rho Guanine Nucleotide Exchange Factors
English An inherited polyneuropathy (PN) observed in Leonberger dogs has clinical similarities to a genetically heterogeneous group of peripheral neuropathies termed Charcot-Marie-Tooth (CMT) disease in humans. The Leonberger disorder is a severe, juvenile-onset, chronic, progressive, and mixed PN, characterized by exercise intolerance, gait abnormalities and muscle atrophy of the pelvic limbs, as well as inspiratory stridor and dyspnea. We mapped a PN locus in Leonbergers to a 250 kb region on canine chromosome 16 (Praw = 1.16×10-10, Pgenome, corrected = 0.006) utilizing a high-density SNP array. Within this interval is the ARHGEF10 gene, a member of the rho family of GTPases known to be involved in neuronal growth and axonal migration, and implicated in human hypomyelination. ARHGEF10 sequencing identified a 10 bp deletion in affected dogs that removes four nucleotides from the 3'-end of exon 17 and six nucleotides from the 5'-end of intron 17 (c.1955_1958+6delCACGGTGAGC). This eliminates the 3'-splice junction of exon 17, creates an alternate splice site immediately downstream in which the processed mRNA contains a frame shift, and generates a premature stop codon predicted to truncate approximately 50% of the protein. Homozygosity for the deletion was highly associated with the severe juvenile-onset PN phenotype in both Leonberger and Saint Bernard dogs. The overall clinical picture of PN in these breeds, and the effects of sex and heterozygosity of the ARHGEF10 deletion, are less clear due to the likely presence of other forms of PN with variable ages of onset and severity of clinical signs. This is the first documented severe polyneuropathy associated with a mutation in ARHGEF10 in any species.
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  • English
Open access status
gold
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https://sonar.ch/global/documents/138929
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