Muscular Dystrophy-Dystroglycanopathy in a Family of Labrador Retrievers with a LARGE 1 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

doi:10.1016/j.nmd.2021.07.016

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Muscular Dystrophy-Dystroglycanopathy in a Family of Labrador Retrievers with a LARGE 1 Mutation

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Muscular Dystrophy-Dystroglycanopathy in a Family of Labrador Retrievers with a LARGE 1 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, …

Neuromuscular disorders : NMD, Vol.31(11), pp.1169-1178

07/28/2021

DOI: 10.1016/j.nmd.2021.07.016

PMCID: PMC8963908

PMID: 34654610

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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.

dog

glycosylation

myopathy

α-dystroglycan

Details

Title: Subtitle: Muscular Dystrophy-Dystroglycanopathy in a Family of Labrador Retrievers with a LARGE 1 Mutation
Creators: G. Diane Shelton - University of California, San Diego
Katie M. Minor - University of Minnesota
Ling T. Guo - University of California, San Diego
Steven G. Friedenberg - University of Minnesota
Jonah N. Cullen - University of Minnesota
Jeffrey M. Hord - University of Iowa
David Venzke - Roy J. and Lucille A. Carver College of Medicine
Mary E. Anderson - Roy J. and Lucille A. Carver College of Medicine
Megan Devereaux - University of Iowa
Sally J. Prouty - Roy J. and Lucille A. Carver College of Medicine
Caryl Handelman - Veterinary Housecalls of Long Island, Commack, NY 11725 United States.
Kevin P. Campbell - University of Iowa
James R. Mickelson - University of Minnesota
Resource Type: Journal article
Publication Details: Neuromuscular disorders : NMD, Vol.31(11), pp.1169-1178
DOI: 10.1016/j.nmd.2021.07.016
PMID: 34654610
PMCID: PMC8963908
ISSN: 0960-8966
eISSN: 1873-2364
Language: English
Date published: 07/28/2021
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984307660102771

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