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A dystroglycan mutation associated with limb-girdle muscular dystrophy
Yuji Hara1, Burcu Balci-Hayta, Takako Yoshida-Moriguchi
1Department of Molecular Physiology and Biophysics, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, USA.
The New England Journal of Medicine
|March 11, 2011
Summary
A mutation in dystroglycan impairs its O-glycosylation, affecting muscle and brain function. This leads to limb-girdle muscular dystrophy and cognitive impairment, highlighting the importance of glycosylation for receptor function.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Dystroglycan is a crucial extracellular matrix receptor in muscle and the central nervous system.
- Proper function of dystroglycan depends on extensive O-glycosylation.
Observation:
- A specific missense mutation (Thr192→Met) in dystroglycan was identified in a patient with limb-girdle muscular dystrophy and cognitive impairment.
- A mouse model with this mutation mirrored the patient's neuromuscular and immunohistochemical abnormalities.
Findings:
- The identified mutation disrupts the O-glycosylation of α-dystroglycan, a critical post-translational modification.
- This disruption inhibits the binding of dystroglycan to laminin, impairing its receptor function in skeletal muscle and the brain.
- The glycosyltransferase LARGE is involved in the aberrant modification pathway.
Implications:
- This study elucidates a molecular mechanism linking dystroglycan dysfunction to muscular dystrophy and cognitive deficits.
- Understanding this glycosylation defect provides insights into potential therapeutic targets for related neurological and muscular disorders.
- The findings underscore the essential role of O-glycosylation in maintaining the integrity and function of dystroglycan in vivo.
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