Journal article
ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome
Nature genetics, Vol.44(5), pp.575-580
05/2012
DOI: 10.1038/ng.2252
PMCID: PMC3371168
PMID: 22522420
Abstract
Walker-Warburg syndrome (WWS) is clinically defined as congenital muscular dystrophy accompanied by a variety of brain and eye malformations. It represents the most severe clinical phenotype in a spectrum of alpha-dystroglycan posttranslational processing abnormalities, which share a defect in laminin binding glycan synthesis
1
. Although six WWS causing genes have been described, only half of all patients can currently be diagnosed genetically
2
. A cell fusion complementation assay using fibroblasts from undiagnosed WWS individuals identified five novel complementation groups. Further evaluation of one group by linkage analysis and targeted sequencing identified recessive mutations in the isoprenoid synthase domain containing (
ISPD
) gene. Confirmation of the pathogenicity of the identified
ISPD
mutations was demonstrated by complementation of fibroblasts with wild-type
ISPD
. Finally, we show that recessive mutations in
ISPD
abolish the initial step in laminin binding glycan synthesis by disrupting dystroglycan
O
-mannosylation. This establishes a novel mechanism for WWS pathophysiology.
Details
- Title: Subtitle
- ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome
- Creators
- Tobias Willer - Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USAHane Lee - Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USAMark Lommel - Centre for Organismal Studies, Department of Cell Chemistry, University of Heidelberg, GermanyTakako Yoshida-Moriguchi - Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USADaniel Beltran Valero de Bernabe - Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USADavid Venzke - Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USASebahattin Cirak - Dubowitz Neuromuscular Centre, Division of Neuroscience, Institute of Child Health & Great Ormond Street Hospital for Children, London, UKHarry Schachter - Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ont., CanadaJiri Vajsar - Division of Neurology, The Hospital for Sick Children, Toronto, Ont., CanadaThomas Voit - University Pierre et Marie Curie, UM 76, Inserm U974, CNRS UMR 7215, AP-HP, Institute of Myology, Paris, FranceFrancesco Muntoni - Dubowitz Neuromuscular Centre, Division of Neuroscience, Institute of Child Health & Great Ormond Street Hospital for Children, London, UKAndrea S Loder - White-Wilson Medical Center, Ft. Walton Beach, Florida, USAWilliam B Dobyns - Department of Pediatrics, University of Chicago, Chicago, Illinois, USAThomas L Winder - PreventionGenetics, Marshfield, WI, USASabine Strahl - Centre for Organismal Studies, Department of Cell Chemistry, University of Heidelberg, GermanyKatherine D Mathews - Department of Pediatrics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USAStanley F Nelson - Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USASteven A Moore - Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USAKevin P Campbell - Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.44(5), pp.575-580
- DOI
- 10.1038/ng.2252
- PMID
- 22522420
- PMCID
- PMC3371168
- NLM abbreviation
- Nat Genet
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Language
- English
- Date published
- 05/2012
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984013112502771
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