Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital muscular dystrophy
| Autor: | Lakshmi Mehta, Kevin P. Campbell, Charles J. Waechter, Tobias Willer, Amy Yang, Bobby G. Ng, Jeffrey S. Rush, Kimiyo Raymond, Hudson H. Freeze, Steven A. Moore |
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| Rok vydání: | 2013 |
| Předmět: |
Male
medicine.medical_specialty Microcephaly Biopsy Endocrinology Diabetes and Metabolism Biology Mannosyltransferases Biochemistry Muscular Dystrophies Article Diagnosis Differential Congenital Disorders of Glycosylation Endocrinology Internal medicine Gene Order Genetics medicine Humans Missense mutation Muscular dystrophy Muscle Skeletal Molecular Biology Muscle biopsy medicine.diagnostic_test Wild type Infant Exons medicine.disease Hypotonia Enzyme Activation Mutation Disease Progression Congenital muscular dystrophy Female medicine.symptom Congenital disorder of glycosylation |
| Zdroj: | Molecular Genetics and Metabolism. 110:345-351 |
| ISSN: | 1096-7192 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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