Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

Aaron M Beedle; Amy J Turner; Yoshiaki Saito; John D Lueck; Steven J Foltz; Marisa J Fortunato; Patricia M Nienaber; Kevin P Campbell

doi:10.1172/JCI63004

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Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

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Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

Aaron M Beedle, Amy J Turner, Yoshiaki Saito, John D Lueck, Steven J Foltz, Marisa J Fortunato, Patricia M Nienaber and Kevin P Campbell

The Journal of clinical investigation, Vol.122(9), pp.3330-3342

09/04/2012

DOI: 10.1172/JCI63004

PMCID: PMC3428090

PMID: 22922256

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Abstract

Dystroglycan is a transmembrane glycoprotein that links the extracellular basement membrane to cytoplasmic dystrophin. Disruption of the extensive carbohydrate structure normally present on α-dystroglycan causes an array of congenital and limb girdle muscular dystrophies known as dystroglycanopathies. The essential role of dystroglycan in development has hampered elucidation of the mechanisms underlying dystroglycanopathies. Here, we developed a dystroglycanopathy mouse model using inducible or muscle-specific promoters to conditionally disrupt fukutin ( Fktn ), a gene required for dystroglycan processing. In conditional Fktn -KO mice, we observed a near absence of functionally glycosylated dystroglycan within 18 days of gene deletion. Twenty-week-old KO mice showed clear dystrophic histopathology and a defect in glycosylation near the dystroglycan O -mannose phosphate, whether onset of Fktn excision driven by muscle-specific promoters occurred at E8 or E17. However, the earlier gene deletion resulted in more severe phenotypes, with a faster onset of damage and weakness, reduced weight and viability, and regenerating fibers of smaller size. The dependence of phenotype severity on the developmental timing of muscle Fktn deletion supports a role for dystroglycan in muscle development or differentiation. Moreover, given that this conditional Fktn -KO mouse allows the generation of tissue- and timing-specific defects in dystroglycan glycosylation, avoids embryonic lethality, and produces a phenotype resembling patient pathology, it is a promising new model for the study of secondary dystroglycanopathy.

Details

Title: Subtitle: Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy
Creators: Aaron M Beedle - Howard Hughes Medical Institute, Departments of Molecular Physiology and Biophysics, Neurology and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Amy J Turner - Howard Hughes Medical Institute, Departments of Molecular Physiology and Biophysics, Neurology and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Yoshiaki Saito - Howard Hughes Medical Institute, Departments of Molecular Physiology and Biophysics, Neurology and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
John D Lueck - Howard Hughes Medical Institute, Departments of Molecular Physiology and Biophysics, Neurology and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Steven J Foltz - Howard Hughes Medical Institute, Departments of Molecular Physiology and Biophysics, Neurology and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Marisa J Fortunato - Howard Hughes Medical Institute, Departments of Molecular Physiology and Biophysics, Neurology and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Patricia M Nienaber - Howard Hughes Medical Institute, Departments of Molecular Physiology and Biophysics, Neurology and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Kevin P Campbell - Howard Hughes Medical Institute, Departments of Molecular Physiology and Biophysics, Neurology and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.122(9), pp.3330-3342
DOI: 10.1172/JCI63004
PMID: 22922256
PMCID: PMC3428090
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Language: English
Date published: 09/04/2012
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984020856202771

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