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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Congenital myasthenic syndromes due to mutations in ALG2 and ALG14
Brain, Volume 136, No. 3, Year 2013
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Description
Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed linkage analysis, whole-exome and whole-genome sequencing to determine the underlying defect in patients with an inherited limb-girdle pattern of myasthenic weakness. We identify ALG14 and ALG2 as novel genes in which mutations cause a congenital myasthenic syndrome. Through analogy with yeast, ALG14 is thought to form a multiglycosyltransferase complex with ALG13 and DPAGT1 that catalyses the first two committed steps of asparagine-linked protein glycosylation. We show that ALG14 is concentrated at the muscle motor endplates and small interfering RNA silencing of ALG14 results in reduced cell-surface expression of muscle acetylcholine receptor expressed in human embryonic kidney 293 cells. ALG2 is an alpha-1,3-mannosyltransferase that also catalyses early steps in the asparagine-linked glycosylation pathway. Mutations were identified in two kinships, with mutation ALG2p.Val68Gly found to severely reduce ALG2 expression both in patient muscle, and in cell cultures. Identification of DPAGT1, ALG14 and ALG2 mutations as a cause of congenital myasthenic syndrome underscores the importance of asparagine-linked protein glycosylation for proper functioning of the neuromuscular junction. These syndromes form part of the wider spectrum of congenital disorders of glycosylation caused by impaired asparagine-linked glycosylation. It is likely that further genes encoding components of this pathway will be associated with congenital myasthenic syndromes or impaired neuromuscular transmission as part of a more severe multisystem disorder. Our findings suggest that treatment with cholinesterase inhibitors may improve muscle function in many of the congenital disorders of glycosylation. © 2013 The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain.
Authors & Co-Authors
Cossins, Judith A.
United Kingdom, Oxford
University of Oxford Medical Sciences Division
Belaya, Katsiaryna
United Kingdom, Oxford
University of Oxford Medical Sciences Division
United Kingdom, Oxford
University of Oxford
Hicks, Debbie
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Salih, Mustafa Abdalla M.
Saudi Arabia, Riyadh
College of Medicine
Finlayson, Sarah
United Kingdom, Oxford
University of Oxford Medical Sciences Division
United Kingdom, Oxford
John Radcliffe Hospital
Carboni, Nicola
Italy, Sardinia
Hospital Bianghi
Liu, Weiwei
United Kingdom, Oxford
University of Oxford Medical Sciences Division
Maxwell, Susan E.
United Kingdom, Oxford
University of Oxford Medical Sciences Division
Zoltowska, Katarzyna
United Kingdom, Oxford
University of Oxford Medical Sciences Division
Farsani, Golara Torabi
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Laval, Steven H.
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Seidhamed, Mohammed Zain
Saudi Arabia, Riyadh
Security Forces Hospital Program Riyadh
Donnelly, Peter K.
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
Bentley, David R.
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
McGowan, Simon J.
United Kingdom, Oxford
Mrc Weatherall Institute of Molecular Medicine
Müller, Juliane S.
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Palace, Jacqueline A.
United Kingdom, Oxford
John Radcliffe Hospital
Lochmüller, Hanns
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Beeson, David M.W.
United Kingdom, Oxford
University of Oxford Medical Sciences Division
Statistics
Citations: 114
Authors: 19
Affiliations: 9
Identifiers
Doi:
10.1093/brain/awt010
e-ISSN:
14602156
Research Areas
Cancer
Genetics And Genomics
Health System And Policy