OMIA 002460-9615 : Muscular dystrophy-dystroglycanopathy, LARGE1-related in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 603590 (gene) , 613154 (trait) , 608840 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2021

Mapping: Shelton et al. (2021) genotypes 4 closely related cases and 8 controls on Illumina CanineHD BeadChips. The authors filtered the genotype data for homozygosity and shared alleles in the four cases and heterozygosity or homozygosity for the alternative allele in the 8 controls. This approach identified two likely candidate regions: "In total, 115 SNPs met this criterion; 91 of these SNPs reside in an ∼12.5 Mb segment on chromosome 10 between bp positions 286 22,958,819–35,483,256; 19 of the SNPs were on chromosome 11 in an ∼5 Mb segment between 15,673,594–20,546,241; and the 5 remaining sporadic SNPs were on chromosome 36" (Shelton et al. 2021). The coordinates refer to the CanFam3.1 genome assembly.

Molecular basis: Shelton et al. (2021) performed illumina whole genome sequence analysis at 17x coverage of one affected dog and compared the variants to the genomes of 522 other dogs from 55 breeds. This identified a single candidate variant, a nonsense variant in the LARGE1 gene chromosome 10 (Chr10 g.30,357,716C>T; c.1363C>T ; p.R455*, ENSCAFT00000074128.1, XM_038680042.1). Genotypes at this variant showed perfect cosegregation with the phenotype in a large pedigree comprising 4 affected puppies in two litters and 9 unaffected dogs. The authors further demonstrated that α-dystroglycan glycosylation in affected puppies was altered compared to controls. Finally, Shelton et al. (2021) demonstrated that the α-dystroglycan in the affected dogs was no longer able to bind laminin.

The LARGE 1 gene encodes like-acetyl-glucosaminyltransferase 1, which participates in the post-translational modification of α-dystroglycan by synthesizing a heteropolysaccharide known as matriglycan, which is required for the binding of α-dystroglycan and extracellular matrix ligands (Inamori et al. 2012).

Clinical features: "Four affected Labrador retriever puppies ... were evaluated for small stature, poor weight gain, bow legged stance, poor suckling, and weakness. In the first week 4 pups required supplemental tube feeding due to poor weight gain, and difficulties in prehension of food and swallowing. One of these 4 pups died during the first week and another pup was euthanized at 2.5 weeks of age. At the time of euthanasia at 6 weeks of age, body weights of the two remaining affected pups were half that of the normal pups (1.3 and 1.4 kg compared to 2.7–2.9 kg). ... Serum CK activities were markedly elevated in all affected pups ranging from 10,587 to 23,638 IU/L (reference 59–895 IU/L)." (Shelton et al. 2021)

Pathology: "Histopathology of skeletal muscle cryosections ... showed degenerative and regenerative changes consistent with a dystrophic phenotype" (Shelton et al. 2021).

Breed: Labrador Retriever.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
LARGE like-glycosyltransferase Canis lupus familiaris 10 NC_051814.1 (30671995..31198842) LARGE Homologene, Ensembl, NCBI gene

Variants

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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
1371 Labrador Retriever Muscular dystrophy-dystroglycanopathy LARGE nonsense (stop-gain) Naturally occurring variant CanFam3.1 10 g.30357716C>T c.1363C>T p.(R455*) 2021 34654610

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.
2021 Shelton, G.D., Minor, K.M., Guo, L.T., Friedenberg, S.G., Cullen, J.N., Hord, J.M., Venzke, D., Anderson, M.E., Devereaux, M., Prouty, S.J., Handelman, C., Campbell, K.P., Mickelson, J.R. :
Muscular dystrophy-dystroglycanopathy in a family of Labrador retrievers with a LARGE1 mutation. Neuromuscul Disord :, 2021. Pubmed reference: 34654610. DOI: 10.1016/j.nmd.2021.07.016.
2012 Inamori, K., Yoshida-Moriguchi, T., Hara, Y., Anderson, M.E., Yu, L., Campbell, K.P. :
Dystroglycan function requires xylosyl- and glucuronyltransferase activities of LARGE. Science 335:93-6, 2012. Pubmed reference: 22223806. DOI: 10.1126/science.1214115.

Edit History


  • Created by Tosso Leeb on 26 Oct 2021
  • Changed by Tosso Leeb on 27 Oct 2021