DAG1 mutations associated with asymptomatic hyperCKemia and hypoglycosylation of α-dystroglycan

Neurology. 2015 Jan 20;84(3):273-9. doi: 10.1212/WNL.0000000000001162. Epub 2014 Dec 12.


Objectives: To identify gene mutations in patients with dystroglycanopathy and prove pathogenicity of those mutations using an in vitro cell assay.

Methods: We performed whole-exome sequencing on 20 patients, who were previously diagnosed with dystroglycanopathy by immunohistochemistry and/or Western blot analysis. We also evaluated pathogenicity of identified mutations for phenotypic recovery in a DAG1-knockout haploid human cell line transfected with mutated DAG1 complementary DNA.

Results: Using exome sequencing, we identified compound heterozygous missense mutations in DAG1 in a patient with asymptomatic hyperCKemia and pathologically mild muscular dystrophy. Both mutations were in the N-terminal region of α-dystroglycan and affected its glycosylation. Mutated DAG1 complementary DNAs failed to rescue the phenotype in DAG1-knockout cells, suggesting that these are pathogenic mutations.

Conclusion: Novel mutations in DAG1 are associated with asymptomatic hyperCKemia with hypoglycosylation of α-dystroglycan. The combination of exome sequencing and a phenotype-rescue experiment on a gene-knockout haploid cell line represents a powerful tool for evaluation of these pathogenic mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Line, Transformed
  • Cohort Studies
  • Creatine Kinase / metabolism*
  • Dystroglycans / genetics*
  • Dystroglycans / metabolism*
  • Dystrophin / metabolism
  • Female
  • Genetic Association Studies
  • Glycosylation
  • Humans
  • Laminin / metabolism
  • Male
  • Metabolic Diseases / complications
  • Metabolic Diseases / genetics*
  • Middle Aged
  • Muscle, Skeletal / pathology
  • Muscular Dystrophies / complications
  • Muscular Dystrophies / diagnosis
  • Muscular Dystrophies / genetics*
  • Mutation / genetics*
  • Phenotype
  • Protein Transport / genetics
  • Transfection


  • DAG1 protein, human
  • Dystrophin
  • Laminin
  • Dystroglycans
  • Creatine Kinase