A COLQ Missense Mutation in Sphynx and Devon Rex Cats with Congenital Myasthenic Syndrome

Abstract

An autosomal recessive neuromuscular disorder characterized by skeletal muscle weakness, fatigability and variable electromyographic or muscular histopathological features has been described in the two related Sphynx and Devon Rex cat breeds (Felis catus). Collection of data from two affected Sphynx cats and their relatives pointed out a single disease candidate region on feline chromosome C2, identified following a genome-wide SNP-based homozygosity mapping strategy. In that region, we further identified COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase) as a good candidate gene, since COLQ mutations were identified in affected humans and dogs with endplate acetylcholinesterase deficiency leading to a synaptic form of congenital myasthenic syndrome (CMS). A homozygous c.1190G>A missense variant located in exon 15 of COLQ, leading to a C397Y substitution, was identified in the two affected cats. C397 is a highly-conserved residue from the C-terminal domain of the protein; its mutation was previously shown to produce CMS in humans, and here we confirmed in an affected Sphynx cat that it induces a loss of acetylcholinesterase clustering at the neuromuscular junction. Segregation of the c.1190G>A variant was 100% consistent with the autosomal recessive mode of inheritance of the disorder in our cat pedigree; in addition, an affected, unrelated Devon Rex cat recruited thereafter was also homozygous for the variant. Genotyping of a panel of 333 cats from 14 breeds failed to identify a single carrier in non-Sphynx and non-Devon Rex cats. Finally, the percentage of healthy carriers in a European subpanel of 81 genotyped Sphynx cats was estimated to be low (3.7%) and 14 control Devon Rex cats were genotyped as wild-type individuals. Altogether, these results strongly support that the neuromuscular disorder reported in Sphynx and Devon Rex breeds is a CMS caused by a unique c.1190G>A missense mutation, presumably transmitted through a founder effect, which strictly and slightly disseminated in these two breeds. The presently available DNA test will help owners avoid matings at risk.

Classification of myasthenia gravis and congenital myasthenic syndromes in dogs and cats

“…Many syndromes resembling but distinct from MG have been recognized in dogs and cats since 1974. 1,2,[5][6][7][8][9][10][11][12][13][14][15][16][17][59][60][61][62][63][64][65][66][67][68][69][70][71] Affected dogs and cats also manifest skeletal muscle weakness and fatigability, but NMJ autoantibody testing for AChRs is negative. Table 3).…”

“…12,13 These CMSs involve a mutation in the collagen-like tail subunit of asymmetric acetylcholinesterase (COLQ) gene, which anchors acetylcholinesterase (AChE) to the basal lamina of the NMJ. 8,10,12,13 In Labrador Retrievers, it is caused by a nonsynonymous mutation in exon 14, and is inherited in an autosomal recessive manner. 8 Reported onset is 2 to 3 weeks of age, electromyography (EMG) is normal, and a decremental response is observed upon RNS.…”

“…10 In Sphynx and Devon Rex cats, the mutation is shared, and is a missense mutation in exon 15, which is inherited in an autosomal recessive manner. 12,13 Reported onset is 3 to 23 weeks of age, affected cats often have decreased skeletal muscle mass and dorsal protrusion of the scapulae. [12][13][14] Electromyography can disclose positive sharp waves and complex repetitive discharges.…”

Congenital Myasthenic Syndrome in a Mixed Breed Dog

“…There is a single report of two mongrel dogs with suspected CMS; however, confirmatory diagnostic testing was not performed ( 10 ). CMS has also been reported in Sphynx and Devon Rex cats as well as Brahman calves ( 11 – 13 ). To the authors’ knowledge, this is the first report describing a confirmed case of CMS in a mixed breed animal.…”

“…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 ).…”