Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital muscular dystrophy

Mol Genet Metab. 2013 Nov;110(3):345-351. doi: 10.1016/j.ymgme.2013.06.016. Epub 2013 Jun 28.

Abstract

Congenital disorders of glycosylation (CDG) are rare genetic defects mainly in the post-translational modification of proteins via attachment of carbohydrate chains. We describe an infant with the phenotype of a congenital muscular dystrophy, with borderline microcephaly, hypotonia, camptodactyly, severe motor delay, and elevated creatine kinase. Muscle biopsy showed muscular dystrophy and reduced α-dystroglycan immunostaining with glycoepitope-specific antibodies in a pattern diagnostic of dystroglycanopathy. Carbohydrate deficient transferrin testing showed a pattern pointing to a CDG type I. Sanger sequencing of DPM1 (dolichol-P-mannose synthase subunit 1) revealed a novel Gly > Val change c.455G > T missense mutation resulting in p.Gly152Val) of unknown pathogenicity and deletion/duplication analysis revealed an intragenic deletion from exons 3 to 7 on the other allele. DPM1 activity in fibroblasts was reduced by 80%, while affinity for the substrate was not depressed, suggesting a decrease in the amount of active enzyme. Transfected cells expressing tagged versions of wild type and the p.Gly152Val mutant displayed reduced binding to DPM3, an essential, non-catalytic subunit of the DPM complex, suggesting a mechanism for pathogenicity. The present case is the first individual described with DPM1-CDG (CDG-Ie) to also have clinical and muscle biopsy findings consistent with dystroglycanopathy.

Keywords: CDG; CDG-Ie; CGH; CK; Congenital disorder of glycosylation; Congenital muscular dystrophy; DLO; DPM; DPM1; DPM1-CDG; Dol-P; Dol-P-Man; Dystroglycanopathy; EEG; ER; GDP-Man; GDP-mannose; GPI; GlcNAc; MRI; N-acetylglucosamine; comparative genomic hybridization; congenital disorder of glycosylation; creatine kinase; dolichol-P-mannose; dolichol-P-mannose synthase; dolichol-linked oligosaccharides; dolichol-phosphate; electroencephalogram; endoplasmic reticulum; glycophosphatidyl inositol; magnetic resonance imaging.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy
  • Congenital Disorders of Glycosylation / diagnosis*
  • Congenital Disorders of Glycosylation / genetics*
  • Diagnosis, Differential
  • Disease Progression
  • Enzyme Activation
  • Exons
  • Female
  • Gene Order
  • Humans
  • Infant
  • Male
  • Mannosyltransferases / genetics*
  • Mannosyltransferases / metabolism
  • Muscle, Skeletal / pathology
  • Muscular Dystrophies / diagnosis*
  • Mutation*

Substances

  • Mannosyltransferases
  • dolichyl-phosphate beta-D-mannosyltransferase