Journal article
G.P.2 Mutations in the human isoprenoid synthase domain containing gene are a common cause of congenital and limb girdle muscular dystrophies
Neuromuscular disorders : NMD, Vol.22(9-10), pp.812-812
10/2012
DOI: 10.1016/j.nmd.2012.06.036
Abstract
The secondary dystroglycanopathies are a recessively inherited diverse group of muscular dystrophies ranging in severity from congenital onset with severe cobblestone lissencephaly (Walker-Warburg Syndrome) to milder forms of limb girdle muscular dystrophy (LGMD). Their hallmark is the reduction of alpha-dystroglycan (ADG) glycosylation and an important part of this glycosylation is a unique O-mannosylation which regulates the interaction between ADG and extracellular matrix proteins including laminin alpha 2, perlecan and agrin. The genetic aetiologies of approximately 50% of the dystroglycanopathies have been attributed to nine genes that are involved in ADG glycosylation. Despite collaborative efforts of several international groups using traditional positional cloning, the causative genes for the unsolved dystroglycanopathy cases had escaped discovery. Recently bi-allelic loss of function mutations in the isoprenoid synthase domain containing (ISPD) have been described in Walker-Warburg syndrome. In a collaborative study with the UK10K Rare Disease Project from the Sanger Institute, using whole exome sequencing techniques, we have now discovered that mutations in ISPD are found in a significant proportion of ADG patients. The mutations identified are milder mutations, and the phenotype of affected patients ranges from muscle-eye-brain like disorders, to congenital muscular dystrophy without brain involvement and to limb girdle muscular dystrophy with or without evidence of brain involvement. While in eubacteria and in choloroblasts of higher plants ISPD orthologues are involved in the synthesis of isoprenoid precursors, this pathway is absent in eukaryotes and vertebrates and; therefore, the function of ISPD remains unknown. The mechanism of ISPD mutations leading to reduction of ADG glycosylation needs to be uncovered; however, our ongoing screening shows that ISPD mutations are a common cause of dystroglycanopathies.
Details
- Title: Subtitle
- G.P.2 Mutations in the human isoprenoid synthase domain containing gene are a common cause of congenital and limb girdle muscular dystrophies
- Creators
- S Cirak - UCL Institute of Child Health, London, United KingdomR.A Foley - UCL Institute of Child Health, London, United KingdomR Herrmann - Essen University, Essen, GermanyT Willer - Iowa University, Iowa City, United StatesS Elisabeth - UCL Institute of Child Health, London, United KingdomM Yau - GSTS Pathology, London, United KingdomL Brodd - GSTS Pathology, London, United KingdomS Torelli - UCL Institute of Child Health, London, United KingdomA Kamynina - UCL Institute of Child Health, London, United KingdomP Vondracek - Brno University Hospital, Brno, Czech RepublicH Roper - Heartlands Hospital, Birmingham, United KingdomC Longman - Yorkhill Hospital, Glasgow, United KingdomR Korinthenberg - University of Freiburg, Freiburg, GermanyG Marrosu - University of Cagliari, Cagliari, ItalyP Nurnberg - Center for Genomics, Cologne, GermanyV Plagnol - UCL Genetics Institute, London, United KingdomM Hurles - Sanger Institute, Cambridge, United KingdomC.A Sewry - UCL Institute of Child Health, London, United KingdomK.P Campbell - Iowa University, Iowa City, United StatesT Voit - Institute de Myologie, Paris, FranceF Muntoni - UCL Institute of Child Health, London, United Kingdom
- Resource Type
- Journal article
- Publication Details
- Neuromuscular disorders : NMD, Vol.22(9-10), pp.812-812
- Publisher
- Elsevier B.V
- DOI
- 10.1016/j.nmd.2012.06.036
- ISSN
- 0960-8966
- eISSN
- 1873-2364
- Language
- English
- Date published
- 10/2012
- Academic Unit
- Iowa Neuroscience Institute; Neurology; Molecular Physiology and Biophysics
- Record Identifier
- 9984068361902771
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