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.
|Number of pages||7|
|Journal||Molecular Genetics and Metabolism|
|State||Published - Nov 2013|
Bibliographical noteFunding Information:
Work done at the Sanford Children's Health Research Center was made possible by the NIH grant R01DK55615 and The Rocket Fund . Work done at the University of Kentucky College of Medicine was supported by the NIH grant GM102129 . K.P.C. is an investigator of the Howard Hughes Medical Institute. The work done at the University of Iowa was also supported in part by a Paul D. Wellstone Muscular Dystrophy Cooperative Research Center grant ( U54NS053672 ).
- Congenital disorder of glycosylation
- Congenital muscular dystrophy
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Molecular Biology