Categories: Muscle phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 603590 (gene) , 613154 (trait) , 608840 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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 (Dog) (VBO_0200800).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: