OMIA 001928-9615 : Myasthenic syndrome, congenital, COLQ-related in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 603034 (trait) , 603033 (gene)

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.

Associated gene:

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

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

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

References


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.

Edit History


  • Created by Frank Nicholas on 06 Sep 2014
  • Changed by Frank Nicholas on 06 Sep 2014
  • Changed by Frank Nicholas on 09 Nov 2016
  • Changed by Frank Nicholas on 30 Jan 2020
  • Changed by Imke Tammen2 on 22 May 2022