Congenital myasthenic syndrome in Golden Retrievers is associated with a novelCOLQmutation

Abstract

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.

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).…”

“…75 A concurrent presynaptic and postsynaptic category is not included in this classification of CMSs in dogs and cats because at the present time such CMSs are not reported in these species. 5,10 This situation might may change as new CMSs are discovered. Despite efforts to classify CMSs in dogs and cats, many suspected CMSs presently cannot be classified because of a lack of identification of an underlying genetic mutation 7,15,16,60,61,64,65,67 Among these suspected CMSs, many are suspected to be postsynaptic because of a lack of postsynaptic AChRs, 7,15,16,64 but these suspected CMSs still cannot be classified, because concurrent presynaptic involvement cannot be excluded because of a lack of knowledge of the suspected underlying genetic mutation, 7,15,16,64 and as such a deficiency although marginal also is reported in some synaptic CMSs in dogs.…”

“…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.…”

“…8 In Golden Retrievers, it is caused by a nonconserved missense mutation in exon 13 that is inherited in an autosomal recessive manner. 10 Reported onset is 6 to 8 weeks of age, EMG is normal, but motor nerve conduction studies can identify a mild decrease in the amplitude of the M wave, and RNS identifies a decremental response. 10 Skeletal muscle and nerve biopsy results are normal, but postsynaptic AChR concentration also is marginally decreased.…”

“…10 Genetic testing for this mutation is available for this breed. 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.…”