Muscular dystrophy-dystroglycanopathy in a family of Labrador retrievers with a LARGE1 mutation

G. Diane Shelton, Katie M. Minor, Ling T. Guo, Steven G. Friedenberg, Jonah N. Cullen, Jeffrey M. Hord, David Venzke, Mary E. Anderson, Megan Devereaux, Sally J. Prouty, Caryl Handelman, Kevin P. Campbell, James R. Mickelson

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1169-1178
Number of pages10
JournalNeuromuscular Disorders
Volume31
Issue number11
Early online dateJul 28 2021
DOIs
StatePublished - Nov 2021

Bibliographical note

Funding 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.

Funding Information:
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.

Funding Information:
This work was supported in part by a Paul D. Wellstone Muscular Dystrophy Specialized Research Center Grant (1U54NS053672 to KPC).

Publisher Copyright:
© 2021 Elsevier B.V.

Keywords

  • Dog
  • Glycosylation
  • Myopathy
  • α-dystroglycan

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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