Alpha-dystroglycan (αDG) is a highly glycosylated cell surface protein with a significant role in cell-to-extracellular matrix interactions in muscle. αDG interaction with extracellular ligands relies on the activity of the LARGE1 glycosyltransferase that synthesizes and extends the heteropolysaccharide matriglycan. Abnormalities in αDG glycosylation and formation of matriglycan are the pathogenic mechanisms for the dystroglycanopathies, a group of congenital muscular dystrophies. Muscle biopsies were evaluated from related 6-week-old Labrador retriever puppies with poor suckling, small stature compared to normal litter mates, bow-legged stance and markedly elevated creatine kinase activities. A dystrophic phenotype with marked degeneration and regeneration, multifocal mononuclear cell infiltration and endomysial fibrosis was identified on muscle cryosections. Single nucleotide polymorphism (SNP) array genotyping data on the family members identified three regions of homozygosity in 4 cases relative to 8 controls. Analysis of whole genome sequence data from one of the cases identified a stop codon mutation in the LARGE1 gene that truncates 40% of the protein. Immunofluorescent staining and western blotting demonstrated the absence of matriglycan in skeletal muscle and heart from affected dogs. Compared to control, LARGE enzyme activity was not detected. This is the first report of a dystroglycanopathy in dogs.
Bibliographical noteFunding Information:
KPC is an investigator of the Howard Hughes Medical Institute. This work was supported in part by a Paul D. Wellstone Muscular Dystrophy Specialized Research Center Grant (1U54NS053672 to KPC). This work was also supported by the Cardiovascular Institutional Research Fellowship (5T32HL007121?45 to JMH). SGF is supported in part by an NIH Special Emphasis Research Career Award (1 K01 OD027058) in Pathology and Comparative Medicine sponsored by the Division of Comparative Medicine, Office of Research Infrastructure Programs. The authors thank Andrew David Miller and Kathleen Kelly for pathologic evaluation of the brain and heart on the affected dog necropsied at Cornell University.
SGF is supported in part by an NIH Special Emphasis Research Career Award (1 K01 OD027058) in Pathology and Comparative Medicine sponsored by the Division of Comparative Medicine, Office of Research Infrastructure Programs.
This work was supported in part by a Paul D. Wellstone Muscular Dystrophy Specialized Research Center Grant (1U54NS053672 to KPC).
© 2021 Elsevier B.V.
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't
- Research Support, N.I.H., Extramural