title: COLQ variant associated with Devon Rex and Sphynx feline hereditary myopathy.
abstract: Some Devon Rex and Sphynx cats have a variably progressive myopathy characterized by appendicular and axial muscle weakness, megaesophagus, pharyngeal weakness and fatigability with exercise. Muscle biopsies from affected cats demonstrated variable pathological changes ranging from dystrophic features to minimal abnormalities. Affected cats have exacerbation of weakness following anticholinesterase dosing, a clue that there is an underlying congenital myasthenic syndrome (CMS). A genome-wide association study and whole-genome sequencing suggested a causal variant for this entity was a c.1190G>A variant causing a cysteine to tyrosine substitution (p.Cys397Tyr) within the C-terminal domain of collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase (COLQ). Alpha-dystroglycan expression, which is associated with COLQ anchorage at the motor end-plate, has been shown to be deficient in affected cats. Eighteen affected cats were identified by genotyping, including cats from the original clinical descriptions in 1993 and subsequent publications. Eight Devon Rex and one Sphynx not associated with the study were identified as carriers, suggesting an allele frequency of ~2.0% in Devon Rex. Over 350 tested cats from other breeds did not have the variant. Characteristic clinical features and variant presence in all affected cats suggest a model for COLQ CMS. The association between the COLQ variant and this CMS affords clinicians the opportunity to confirm diagnosis via genetic testing and permits owners and breeders to identify carriers in the population. Moreover, accurate diagnosis increases available therapeutic options for affected cats based on an understanding of the pathophysiology and experience from human CMS associated with COLQ variants.
authors.affiliation: Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri - Columbia, Columbia, MO, 65211, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gandolfi
authors.affiliation: Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California - Davis, Davis, CA, 95616, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Grahn
authors.affiliation: Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri - Columbia, Columbia, MO, 65211, USA.
authors.forename: Erica K
authors.initials: EK
authors.lastname: Creighton
authors.affiliation: The William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California - Davis, Davis, CA, 95616, USA.
authors.forename: D Colette
authors.initials: DC
authors.lastname: Williams
authors.affiliation: Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California - Davis, Davis, CA, 95616, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dickinson
authors.affiliation: Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California - Davis, Davis, CA, 95616, USA.
authors.forename: Beverly K
authors.initials: BK
authors.lastname: Sturges
authors.affiliation: Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California - Davis, Davis, CA, 95616, USA.
authors.forename: Ling T
authors.initials: LT
authors.lastname: Guo
authors.affiliation: Department of Pathology, University of California - San Diego, La Jolla, CA, 92093, USA.
authors.forename: G Diane
authors.initials: GD
authors.lastname: Shelton
authors.affiliation: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3508 TD, Utrecht, The Netherlands.
authors.forename: Peter A J
authors.initials: PA
authors.lastname: Leegwater
authors.affiliation: Dipartimento di Scienze Veterinarie e Sanità Pubblica, University of Milan, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Longeri
authors.affiliation: Centre for Veterinary Education, University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Malik
authors.affiliation: Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri - Columbia, Columbia, MO, 65211, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lyons
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics*; D000818:Animals; D001947:Breeding; D002371:Cat Diseases / Q000235:genetics*; D002415:Cats / Q000235:genetics*; D003094:Collagen / Q000235:genetics*; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D009124:Muscle Proteins / Q000235:genetics*; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D009124:Muscle Proteins; D003094:Collagen; D000110:Acetylcholinesterase
keywords: Felis catus silvestris; collagen-like tail subunit of asymmetric acetylcholinesterase; congenital myasthenic syndrome; domestic cat