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

Amy C Yang; Bobby G Ng; Steven A Moore; Jeffrey Rush; Charles J Waechter; Kimiyo M Raymond; Tobias Willer; Kevin P Campbell; Hudson H Freeze; Lakshmi Mehta

doi:10.1016/j.ymgme.2013.06.016

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

Journal article

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

Amy C Yang, Bobby G Ng, Steven A Moore, Jeffrey Rush, Charles J Waechter, Kimiyo M Raymond, Tobias Willer, Kevin P Campbell, Hudson H Freeze and Lakshmi Mehta

Molecular genetics and metabolism, Vol.110(3), pp.345-351

11/2013

DOI: 10.1016/j.ymgme.2013.06.016

PMCID: PMC3800268

PMID: 23856421

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https://www.ncbi.nlm.nih.gov/pmc/articles/3800268View

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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. •Concomitant finding of dystroglycanopathy and N-glycosylation defect•Novel missense mutation and an intragenic deletion in DPM1•First description of an O-mannosylation defect in an affected individual with DPM1-CDG

Dystroglycanopathy

DPM1

CDG-Ie

Congenital disorder of glycosylation

Congenital muscular dystrophy

DPM1-CDG

Details

Title: Subtitle: Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital muscular dystrophy
Creators: Amy C Yang - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Bobby G Ng - Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
Steven A Moore - Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
Jeffrey Rush - Department of Molecular and Cellular Biochemistry, Chandler Medical Center, College of Medicine, University of Kentucky, Lexington, KY, USA
Charles J Waechter - Department of Molecular and Cellular Biochemistry, Chandler Medical Center, College of Medicine, University of Kentucky, Lexington, KY, USA
Kimiyo M Raymond - Department of Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN, USA
Tobias Willer - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
Kevin P Campbell - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
Hudson H Freeze - Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
Lakshmi Mehta - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Resource Type: Journal article
Publication Details: Molecular genetics and metabolism, Vol.110(3), pp.345-351
DOI: 10.1016/j.ymgme.2013.06.016
PMID: 23856421
PMCID: PMC3800268
NLM abbreviation: Mol Genet Metab
ISSN: 1096-7192
eISSN: 1096-7206
Publisher: Elsevier Inc
Grant note: name: NIH, award: R01DK55615; name: The Rocket Fund, award: GM102129; name: NIH, award: U54NS053672; name: Paul D. Wellstone Muscular Dystrophy Cooperative Research Center
Language: English
Date published: 11/2013
Academic Unit: Neurology; Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute
Record Identifier: 9984020880802771

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