Document Detail


Mutant glycosyltransferase and altered glycosylation of alpha-dystroglycan in the myodystrophy mouse.
MedLine Citation:
PMID:  11381262     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Spontaneous and engineered mouse mutants have facilitated our understanding of the pathogenesis of muscular dystrophy and they provide models for the development of therapeutic approaches. The mouse myodystrophy (myd) mutation produces an autosomal recessive, neuromuscular phenotype. Homozygotes have an abnormal gait, show abnormal posturing when suspended by the tail and are smaller than littermate controls. Serum creatine kinase is elevated and muscle histology is typical of a progressive myopathy with focal areas of acute necrosis and clusters of regenerating fibers. Additional aspects of the phenotype include sensorineural deafness, reduced lifespan and decreased reproductive fitness. The myd mutation maps to mouse chromosome 8 at approximately 33 centimorgans (cM) (refs. 2, 4-7). Here we show that the gene mutated in myd encodes a glycosyltransferase, Large. The human homolog of this gene (LARGE) maps to chromosome 22q. In myd, an intragenic deletion of exons 4-7 causes a frameshift in the resultant mRNA and a premature termination codon before the first of the two catalytic domains. On immunoblots, a monoclonal antibody to alpha-dystroglycan (a component of the dystrophin-associated glycoprotein complex) shows reduced binding in myd, which we attribute to altered glycosylation of this protein. We speculate that abnormal post-translational modification of alpha-dystroglycan may contribute to the myd phenotype.
Authors:
P K Grewal; P J Holzfeind; R E Bittner; J E Hewitt
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Nature genetics     Volume:  28     ISSN:  1061-4036     ISO Abbreviation:  Nat. Genet.     Publication Date:  2001 Jun 
Date Detail:
Created Date:  2001-05-30     Completed Date:  2001-07-05     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  151-4     Citation Subset:  IM    
Affiliation:
Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/AF029893;  M80599;  Z68006
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Catalytic Domain
Cloning, Molecular
Cytoskeletal Proteins / metabolism*
Dystroglycans
Glycosylation
Membrane Glycoproteins / metabolism*
Mice
Mice, Mutant Strains
Molecular Sequence Data
Muscle, Skeletal
Muscular Dystrophies / genetics*,  metabolism,  pathology
Mutation*
N-Acetylglucosaminyltransferases / genetics*,  metabolism
Neoplasm Proteins*
Protein Processing, Post-Translational
Sequence Homology, Amino Acid
Chemical
Reg. No./Substance:
0/Cytoskeletal Proteins; 0/DAG1 protein, human; 0/Membrane Glycoproteins; 0/Neoplasm Proteins; 146888-27-9/Dystroglycans; EC 2.4.1.-/LARGE protein, human; EC 2.4.1.-/N-Acetylglucosaminyltransferases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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