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

TY - JOUR

T1 - 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

AU - Frost, Amy R

AU - Böhm, Sabrina V

AU - Sewduth, Raj N

AU - Josifova, Dragana

AU - Ogilvie, Caroline Mackie

AU - Izatt, Louise

AU - Roberts, Roland G

PY - 2010/7

Y1 - 2010/7

N2 - 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.

AB - 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.

KW - Adolescent

KW - Apraxias/complications

KW - Base Pairing/genetics

KW - Child

KW - Dystroglycans/genetics

KW - Face

KW - Facies

KW - Female

KW - Heterozygote

KW - Humans

KW - Muscle Hypotonia/complications

KW - Muscular Diseases/complications

KW - Neurodegenerative Diseases/complications

KW - Sequence Deletion/genetics

U2 - 10.1038/ejhg.2010.28

DO - 10.1038/ejhg.2010.28

M3 - Article

C2 - 20234391

VL - 18

SP - 852

EP - 855

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 7

ER -