title: Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital muscular dystrophy.
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.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Yang
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA.
authors.forename: Bobby G
authors.initials: BG
authors.lastname: Ng
authors.affiliation: Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.affiliation: Department of Molecular and Cellular Biochemistry, Chandler Medical Center, College of Medicine, University of Kentucky, Lexington, KY.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rush
authors.affiliation: Department of Molecular and Cellular Biochemistry, Chandler Medical Center, College of Medicine, University of Kentucky, Lexington, KY.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Waechter
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN.
authors.forename: Kimiyo M
authors.initials: KM
authors.lastname: Raymond
authors.affiliation: 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.
authors.forename: Tobias
authors.initials: T
authors.lastname: Willer
authors.affiliation: 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.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA.
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Mehta
mesh_terms: D001706:Biopsy; D018981:Congenital Disorders of Glycosylation / Q000175:diagnosis* / Q000235:genetics*; D003937:Diagnosis, Differential; D018450:Disease Progression; D004789:Enzyme Activation; D005091:Exons; D005260:Female; D023061:Gene Order; D006801:Humans; D007223:Infant; D008297:Male; D008364:Mannosyltransferases / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology; D009136:Muscular Dystrophies / Q000175:diagnosis*; D009154:Mutation
chemical_list: D008364:Mannosyltransferases; C022755:dolichyl-phosphate beta-D-mannosyltransferase
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