Heterozygous deletion of a 2-megabase region including the dystroglycan gene in a patient with mild myopathy, facial hypotonia, oral-motor dyspraxia and white matter abnormalities
Résumé
Dystroglycan is a protein which binds directly to two proteins defective in muscular dystrophies (dystrophin and laminin α2) 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, FKRP). It is surprising, therefore, that to our knowledge no mutations of the human dystroglycan gene itself have yet been reported. Here we describe a patient with a heterozygous de novo deletion of a ~2-megabase 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 (CK), oral-motor dyspraxia and facial hypotonia but minimal clinically significant involvement of other muscles. As these symptoms are a subset of those seen 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 seen in the Dag1+/- mouse is not seen in the patient. Although we cannot demonstrate 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.
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