Journal article
Mutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies Associated with Hypoglycosylation of α-Dystroglycan
American journal of human genetics, Vol.93(1), pp.29-41
07/11/2013
DOI: 10.1016/j.ajhg.2013.05.009
PMCID: PMC3710768
PMID: 23768512
Abstract
Congenital muscular dystrophies with hypoglycosylation of α-dystroglycan (α-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of α-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated α-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including α-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced α-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of α-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of α-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-DG.
Details
- Title: Subtitle
- Mutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies Associated with Hypoglycosylation of α-Dystroglycan
- Creators
- Keren J Carss - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UKElizabeth Stevens - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UKA. Reghan Foley - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UKSebahattin Cirak - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UKMoniek Riemersma - Department of Neurology, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Center, 6525 HB Nijmegen, the NetherlandsSilvia Torelli - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UKAlexander Hoischen - Department of Human Genetics, Nijmegen Center for Molecular Life Sciences, Institute for Genetic and Metabolic Disease, Radboud University Medical Center, 6500 HB Nijmegen, the NetherlandsTobias Willer - Howard Hughes Medical Institute and the Departments of Neurology, Internal Medicine, and Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USAMonique van Scherpenzeel - Department of Laboratory Medicine, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Center, 6525 HB Nijmegen, the NetherlandsSteven A Moore - Department of Pathology, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USASonia Messina - Department of Neuroscience, University of Messina, Azienda Ospedaliera Universitaria Policlinico “G. Martino,” Via C. Valeria 1, 98125 Messina, ItalyEnrico Bertini - Laboratory of Molecular Medicine, Bambino Gesù Children’s Research Hospital, 00146 Rome, ItalyCarsten G Bönnemann - Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-3705, USAJose E Abdenur - Division of Metabolic Disorders, Children’s Hospital of Orange County, Orange, CA 92868-3874, USACarla M Grosmann - Departments of Neurosciences and Pediatrics, School of Medicine, University of California, San Diego, Rady Children’s Hospital, San Diego, CA 92123, USAAkanchha Kesari - Research Center for Genetic Medicine, Children’s National Medical Center, Washington, DC 20010, USAJaya Punetha - Research Center for Genetic Medicine, Children’s National Medical Center, Washington, DC 20010, USARos Quinlivan - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UKLeigh B Waddell - Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, Westmead, Sydney, NSW 2145, AustraliaHelen K Young - Department of Neurogenetics, Children’s Hospital at Westmead, Westmead, Sydney, NSW 2145, AustraliaElizabeth Wraige - Department of Paediatric Neurology, Evelina Children’s Hospital, Guy’s and St. Thomas’ NHS Foundation Trust, Lambeth Palace Road, London SE1 7EH, UKShu Yau - DNA Laboratory, GSTS Pathology, London SE1 9RT, UKLina Brodd - DNA Laboratory, GSTS Pathology, London SE1 9RT, UKLucy Feng - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UKCaroline Sewry - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UKDaniel G MacArthur - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USAKathryn N North - Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, Westmead, Sydney, NSW 2145, AustraliaEric Hoffman - Research Center for Genetic Medicine, Children’s National Medical Center, Washington, DC 20010, USADerek L Stemple - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UKMatthew E Hurles - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UKHans van Bokhoven - Department of Human Genetics, Nijmegen Center for Molecular Life Sciences, Radboud University Medical Centre, 6500 HB Nijmegen, the NetherlandsKevin P Campbell - Howard Hughes Medical Institute and the Departments of Neurology, Internal Medicine, and Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USADirk J Lefeber - Department of Neurology, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Center, 6525 HB Nijmegen, the NetherlandsYung-Yao Lin - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UKFrancesco Muntoni - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UK
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.93(1), pp.29-41
- DOI
- 10.1016/j.ajhg.2013.05.009
- PMID
- 23768512
- PMCID
- PMC3710768
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 07/11/2013
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute
- Record Identifier
- 9984020631702771
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