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Congenital myasthenic syndrome in Golden Retrievers is associated with a novel COLQ mutation

Tsai, Kate L., Vernau, Karen M., Winger, Kathryn, Zwueste, Danielle M., Sturges, Beverly K., Knipe, Marguerite, Williams, D. Colette, Anderson, Kendall J., Evans, Jacquelyn M., Guo, Ling T., Clark, Leigh Anne, Shelton, G. Diane
Journal of veterinary internal medicine 2020 v.34 no.1 pp. 258-265
Golden Retriever, Labrador Retriever, acetylcholine, acetylcholinesterase, amino acid substitution, blood, cholinergic receptors, databases, dog diseases, exons, genetic disorders, histology, homozygosity, muscle contraction, muscles, neuromuscular disorders, point mutation, polymerase chain reaction, puppies, skeletal muscle, synapse, weaning, California
BACKGROUND: Congenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission that may be presynaptic, synaptic, or postsynaptic. Causative mutations have been identified in 4 breeds including the Labrador Retriever, Jack Russell Terrier, Heideterrier, and Danish Pointing Dog. HYPOTHESIS/OBJECTIVE: Clinical and genetic characterization of a neuromuscular disorder in Golden Retriever (GR) puppies. ANIMALS: Four GR puppies from California were evaluated for generalized muscle weakness beginning at weaning. Biological specimens were collected from the affected puppies, and familial information was obtained. Blood or buccal swabs were obtained from 63 unaffected GRs. METHODS: Complete physical, neurological, electrodiagnostic, and histological evaluations and biochemical quantification of muscle acetylcholine receptors were performed. Polymerase chain reaction was used to amplify the 17 exons of COLQ, and sequences were obtained by Sanger sequencing. Variant frequency was assessed in unrelated GRs and a public database. RESULTS: Clinical, neurological, and electrodiagnostic evaluations confirmed a disorder of neuromuscular transmission in a GR family. Sequencing of all exons and splice sites of a primary candidate gene, COLQ, identified a point mutation that predicts an amino acid substitution (G294R). The primary COLQ transcript was absent from affected muscle samples. All affected puppies were homozygous for the mutation, which was not detected outside this GR family or in other breeds. CONCLUSIONS AND CLINICAL IMPORTANCE: We confirmed the diagnosis of a CMS in GR puppies and identified a novel COLQ mutation. The COLQ gene encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of skeletal muscle contraction by clearing acetylcholine at the neuromuscular junction. Clinicians and breeders should be aware of this CMS in GR puppies with an early onset of weakness.