COLQ variant associated with Devon Rex and Sphynx feline hereditary myopathy

Abstract

SummarySome 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.

Applications and efficiencies of the first cat 63K DNA array

“…Transmission distortion testing (TDT) has been successful with only 7–13 discordant sib-pairs in canine studies 81 , 82 . The feline array has also proven its utility within breeds and supported the genetic dissection of simple 49 , 61 , 72 , 75 , 83 , 84 and complex traits 52 , 85 , 86 . The array clearly shows significant association power for traits under selection or recessive traits.…”

Whole genome sequencing in cats, identifies new models for blindness in AIPL1 and somite segmentation in HES7

“…Besides traditional rodent models, WGS has been used in cattle [ 68 ] and dogs [ 69 – 71 ] to identify disease mutations, however, the datasets have included hundreds of individuals for comparison. More recently, a WGS of a single cat was used to confirm a previously identified phenotypic variant for White [ 72 ] and a single cat compared to a variant database including 18 cats identified a feline model for Congenital Myasthenic Syndrome [ 47 , 73 ]. However, the cat variant database needs to be improved for continued success, particularly for genetic studies in non-pedigreed, random bred cats [ 38 , 74 , 75 ].…”

Congenital Myasthenic Syndrome in a Mixed Breed Dog

“…A CHRNE mutation was also identified as the cause of CMS in Brahman calves ( 13 ). CMS in Labrador Retrievers and Sphynx and Devon Rex cats is the result of a mutation in the COLQ gene, which encodes the collagenous tail of acetylcholinesterase (AChE) ( 5 , 6 , 8 , 11 , 12 ). In the Old Danish Pointing dog breed, however, CMS is associated with pre-synaptic dysfunction of neuromuscular transmission and a mutation in the choline acetyl-transferase ( CHAT ) gene ( 6 ).…”