title: An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs.
abstract: 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.
authors.affiliation: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America.
authors.forename: Kari J
authors.initials: KJ
authors.lastname: Ekenstedt
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Doreen
authors.initials: D
authors.lastname: Becker
authors.affiliation: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Minor
authors.affiliation: Comparative Neuromuscular Laboratory, Department of Pathology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: G Diane
authors.initials: GD
authors.lastname: Shelton
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Patterson
authors.affiliation: Small Animal Clinic, Neruology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Tim
authors.initials: T
authors.lastname: Bley
authors.affiliation: Neurocenter, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Oevermann
authors.affiliation: Institute of Neuropathology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bilzer
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Tosso
authors.initials: T
authors.lastname: Leeb
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
authors.affiliation: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Mickelson
mesh_terms: D000367:Age Factors; D017668:Age of Onset; D000818:Animals; D016022:Case-Control Studies; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D005260:Female; D017353:Gene Deletion; D055106:Genome-Wide Association Study; D006720:Homozygote; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011115:Polyneuropathies / Q000235:genetics* / Q000662:veterinary*; D022821:RNA Splice Sites; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D022821:RNA Splice Sites; D064067:Rho Guanine Nucleotide Exchange Factors