Heterozygous deletion of a 2-Mb region including the dystroglycan gene in a patient with mild myopathy, facial hypotonia, oral-motor dyspraxia and white matter abnormalities

Dystroglycan is a protein which binds directly to two proteins defective in muscular dystrophies (dystrophin and laminin alpha2) and whose own aberrant post-translational modification is the common aetiological route of neuromuscular diseases associated with mutations in genes encoding at least six...

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Bibliographic Details
Published in:European journal of human genetics : EJHG 2010-07, Vol.18 (7), p.852-855
Main Authors: FROST, Amy R, BÖHM, Sabrina V, SEWDUTH, Raj N, JOSIFOVA, Dragana, OGILVIE, Caroline Mackie, IZATT, Louise, ROBERTS, Roland G
Format: Article
Language:English
Subjects:
Adolescent
Apraxias - complications
Apraxias - genetics
Base Pairing - genetics
Biological and medical sciences
Child
Diseases of striated muscles. Neuromuscular diseases
Dystroglycans - genetics
Face
Facies
Female
Fundamental and applied biological sciences. Psychology
General aspects. Genetic counseling
Genetics of eukaryotes. Biological and molecular evolution
Heterozygote
Humans
Medical genetics
Medical sciences
Molecular and cellular biology
Muscle Hypotonia - complications
Muscle Hypotonia - genetics
Muscular Diseases - complications
Muscular Diseases - genetics
Neurodegenerative Diseases - complications
Neurodegenerative Diseases - genetics
Neurology
Sequence Deletion - genetics
Short Report
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Summary:Dystroglycan is a protein which binds directly to two proteins defective in muscular dystrophies (dystrophin and laminin alpha2) and whose own aberrant post-translational modification is the common aetiological route of neuromuscular diseases associated with mutations in genes encoding at least six other proteins (POMT1, POMT2, POMGnT1, LARGE, FKTN and FKRP). It is surprising, therefore, that to our knowledge no mutations of the human dystroglycan gene itself have yet been reported. In this study, we describe a patient with a heterozygous de novo deletion of a approximately 2-Mb region of chromosome 3, which includes the dystroglycan gene (DAG1). The patient is a 16-year-old female with learning difficulties, white matter abnormalities, elevated serum creatine kinase, oral-motor dyspraxia and facial hypotonia but minimal clinically significant involvement of other muscles. As these symptoms are a subset of those observed in disorders of dystroglycan glycosylation (muscle-eye-brain disease and Warker-Warburg syndrome), we assess the likely contribution to her phenotype of her heterogosity for a null mutation of DAG1. We also show that the transcriptional compensation observed in the Dag1(+/-) mouse is not observed in the patient. Although we cannot show that haploinsufficiency of DAG1 is the sole cause of this patient's myopathy and white matter changes, this case serves to constrain our ideas of the severity of the phenotypic consequences of heterozygosity for null DAG1 mutations.
ISSN:1018-4813
1476-5438
DOI:10.1038/ejhg.2010.28