Journal article
ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies
Brain (London, England : 1878), Vol.136(1), pp.269-281
01/2013
DOI: 10.1093/brain/aws312
PMCID: PMC3562076
PMID: 23288328
Abstract
Dystroglycanopathies are a clinically and genetically diverse group of recessively inherited conditions ranging from the most severe of the congenital muscular dystrophies, Walker–Warburg syndrome, to mild forms of adult-onset limb-girdle muscular dystrophy. Their hallmark is a reduction in the functional glycosylation of α-dystroglycan, which can be detected in muscle biopsies. An important part of this glycosylation is a unique
O
-mannosylation, essential for the interaction of α-dystroglycan with extracellular matrix proteins such as laminin-α2. Mutations in eight genes coding for proteins in the glycosylation pathway are responsible for ∼50% of dystroglycanopathy cases. Despite multiple efforts using traditional positional cloning, the causative genes for unsolved dystroglycanopathy cases have escaped discovery for several years. In a recent collaborative study, we discovered that loss-of-function recessive mutations in a novel gene, called isoprenoid synthase domain containing (
ISPD
), are a relatively common cause of Walker–Warburg syndrome. In this article, we report the involvement of the
ISPD
gene in milder dystroglycanopathy phenotypes ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy and identified allelic
ISPD
variants in nine cases belonging to seven families. In two ambulant cases, there was evidence of structural brain involvement, whereas in seven, the clinical manifestation was restricted to a dystrophic skeletal muscle phenotype. Although the function of
ISPD
in mammals is not yet known, mutations in this gene clearly lead to a reduction in the functional glycosylation of α-dystroglycan, which not only causes the severe Walker–Warburg syndrome but is also a common cause of the milder forms of dystroglycanopathy.
Details
- Title: Subtitle
- ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies
- Creators
- Sebahattin Cirak - 1 Dubowitz Neuromuscular Centre, UCL Institute of Child Health, University College London, WC1N 1EH London, UKAileen Reghan Foley - 1 Dubowitz Neuromuscular Centre, UCL Institute of Child Health, University College London, WC1N 1EH London, UKRalf Herrmann - 2 Zentrum fuer Kinderheilkunde, Paediatrie I, University Hospital Essen, 45145 Essen, GermanyTobias Willer - 3 Howard Hughes Medical Institute, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USAShu Yau - 7 DNA Laboratory, GSTS Pathology, Guy’s Hospital, SE1 9RT, London, UKElizabeth Stevens - 1 Dubowitz Neuromuscular Centre, UCL Institute of Child Health, University College London, WC1N 1EH London, UKSilvia Torelli - 1 Dubowitz Neuromuscular Centre, UCL Institute of Child Health, University College London, WC1N 1EH London, UKLina Brodd - 7 DNA Laboratory, GSTS Pathology, Guy’s Hospital, SE1 9RT, London, UKAlisa Kamynina - 1 Dubowitz Neuromuscular Centre, UCL Institute of Child Health, University College London, WC1N 1EH London, UKPetr Vondracek - 8 University Hospital Brno, Department of Neurology, 62500 Brno, Brno, Czech RepublicHelen Roper - 9 Department Paediatrics, Birmingham Heartlands Hospital, B9 5SS Birmingham, UKCheryl Longman - 10 Department of Clinical Genetics, Yorkhill Hospital, G3 8SJ Glasgow, UKRudolf Korinthenberg - 11 Division of Neuropaediatrics and Muscular Disorders, Department of Paediatrics and Adolescent Medicine, University Hospital, Albert-Ludwigs University, 79106, Freiburg im Breisgau, GermanyGianni Marrosu - 12 Neuromuscular Unit, Multiple Sclerosis Centre, University of Cagliari, 09124, Cagliari, ItalyPeter Nürnberg - 13 Cologne Centre for Genomics (CCG), Universität zu Köln, 50931, Cologne, GermanyDaniel E Michele - 14 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USAVincent Plagnol - 15 UCL Genetics Institute, University College London, WC1E 6BT, London, UKMatt Hurles - 16 Wellcome Trust Sanger Institute, Hinxton, CB10 1SA Cambridge, UKSteven A Moore - 17 Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USACaroline A Sewry - 1 Dubowitz Neuromuscular Centre, UCL Institute of Child Health, University College London, WC1N 1EH London, UKKevin P Campbell - 3 Howard Hughes Medical Institute, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USAThomas Voit - 19 University Pierre et Marie Curie Paris VI, UM 76, INSERM U 974, CNRS UMR 7215, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, FranceFrancesco Muntoni - 1 Dubowitz Neuromuscular Centre, UCL Institute of Child Health, University College London, WC1N 1EH London, UK
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.136(1), pp.269-281
- Publisher
- Oxford University Press
- DOI
- 10.1093/brain/aws312
- PMID
- 23288328
- PMCID
- PMC3562076
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Language
- English
- Date published
- 01/2013
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute
- Record Identifier
- 9984020895302771
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