OMIA:001928-9615 : Myasthenic syndrome, congenital, COLQ-related in Canis lupus familiaris
Categories: Muscle phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 603034 (trait) , 603033 (gene)
Links to MONDO diseases:
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2014
Species-specific name: Congenital myasthenic syndromes
Species-specific symbol: CMS
Mapping: Having access to only two affected members of a single family, Rinz et al. (2014) were not able to conduct a GWAS to map this disorder. Instead they examined haplotype inheritance in the region of 18 comparative candidate genes (based on genes with known causal mutations for various types of CMS in humans), using relevant SNPs from the 173,662 SNPs in the Illumina CanineHD Infinium BeadChip, in the two affected littermates, five normal littermates and the two normal (but related) parents. Only one candidate gene (COLQ; officially known as LOC608697) [on chromosome CFA23] showed concordant inheritance.
Molecular basis: Subsequent sequencing by Rinz et al. (2014) of the primary candidate gene (COLQ or LOC608697; see Mapping section above) revealed a causal mutation as "a variant in exon 14 (c.1010T>C) that results in the substitution of a conserved amino acid (I337T) within the C-terminal domain. Both affected puppies were homozygous for this variant, and 16 relatives were heterozygous, while 288 unrelated Labrador Retrievers and 112 dogs of other breeds were wild-type."
Sequencing the functional candidate gene COLQ in four affected Golden Retriever puppies from a single breeder enabled Tsai et al. (2020) to identify "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."
Clinical features: Affected puppies present with a history of generalised skeletal muscle weakness and fatigue with an onset in the first weeks to months of life (Mignan et al., 2020). As reported by Rinz et al. (2014): "Neurological examination was consistent with a generalized neuromuscular disease with marked short-strided tetraparesis that worsened with exercise. Postural reactions were preserved with the exception of hopping which was diminished in all limbs when the puppies were made to bear full weight. Spinal reflexes including the patellar, cranial tibial, and flexor withdrawals were reduced in all limbs. A pyridostigmine bromide challenge resulted in worsening of muscle weakness." Clinical signs often progress despite treatment, and most reported cases have resulted in death or euthanasia of affected puppies (Mignan et al., 2020). [IT thanks DVM student Lily Cai for contributions in April 2022]
Pathology: As a result of the COLQ mutation, acetylcholinesterase is anchored to the basal lamina of the neuromuscular junction (NMJ). Measurement of the compound muscle action potential through electrodiagnostic testing after repetitive nerve stimulation shows a decremental response, which is consistent with failure of neuromuscular transmission (Tsai et al., 2020). A NMJ antibody testing for acetylcholinesterase is negative (Mignan et al., 2020). [IT thanks DVM student Lily Cai, who provided the basis of this contribution in April 2022]
Breeds: Golden Retriever, Labrador Retriever.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|LOC608697||2-hydroxyacyl-CoA lyase 1||Canis lupus familiaris||23||NC_051827.1 (27572135..27700471)||LOC608697||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|1151||Golden Retriever||Myasthenic syndrome, congenital, COLQ-related||LOC608697||missense||Naturally occurring variant||CanFam3.1||23||g.27175559G>A||c.880G>A||p.(G294R)||2020||31769119|
|900||Labrador Retriever||Myasthenic syndrome, congenital||LOC608697||missense||Naturally occurring variant||CanFam3.1||23||g.27176737T>C||c.1010T>C||p.(I337T)||XM_858278.5; XP_863371.1||2014||25166616||Genomic position in CanFam3.1 provided by Robert Kuhn|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2020||Mignan, T., Targett, M., Lowrie, M. :|
|Classification of myasthenia gravis and congenital myasthenic syndromes in dogs and cats. J Vet Intern Med 34:1707-1717, 2020. Pubmed reference: 32668077 . DOI: 10.1111/jvim.15855.|
|Tsai, K.L., Vernau, K.M., Winger, K., Zwueste, D.M., Sturges, B.K., Knipe, M., Williams, D.C., Anderson, K.J., Evans, J.M., Guo, L.T., Clark, L.A., Shelton, G.D. :|
|Congenital myasthenic syndrome in Golden Retrievers is associated with a novel COLQ mutation. J Vet Intern Med 34:258-265, 2020. Pubmed reference: 31769119 . DOI: 10.1111/jvim.15667.|
|2018||Legay, C. :|
|Congenital myasthenic syndromes with acetylcholinesterase deficiency, the pathophysiological mechanisms. Ann N Y Acad Sci 1413:104-110, 2018. Pubmed reference: 29405353 . DOI: 10.1111/nyas.13595.|
|2016||Shelton, G.D. :|
|Myasthenia gravis and congenital myasthenic syndromes in dogs and cats: A history and mini-review. Neuromuscul Disord 26:331-4, 2016. Pubmed reference: 27080328 . DOI: 10.1016/j.nmd.2016.03.002.|
|2014||Rinz, C.J., Levine, J., Minor, K.M., Humphries, H.D., Lara, R., Starr-Moss, A.N., Guo, L.T., Williams, D.C., Shelton, G.D., Clark, L.A. :|
|A COLQ missense mutation in Labrador Retrievers having congenital myasthenic syndrome. PLoS One 9:e106425, 2014. Pubmed reference: 25166616 . DOI: 10.1371/journal.pone.0106425.|
- Created by Frank Nicholas on 06 Sep 2014
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