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Novel SEA and LG2 Agrin mutations causing congenital Myasthenic syndrome

BACKGROUND: Congenital myasthenic syndrome caused by mutations in AGRN, a gene encoding a protein with a crucial function at the neuromuscular junction, is a rare disorder. There are few studies in this area. We here present two cases with novel mutations of AGRN of which we further investigated pos...

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Autores principales: Xi, Jianying, Yan, Chong, Liu, Wei-Wei, Qiao, Kai, Lin, Jie, Tian, Xia, Wu, Hui, Lu, Jiahong, Wong, Lee-Jun, Beeson, David, Zhao, Chongbo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735900/
https://www.ncbi.nlm.nih.gov/pubmed/29258548
http://dx.doi.org/10.1186/s13023-017-0732-z
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author Xi, Jianying
Yan, Chong
Liu, Wei-Wei
Qiao, Kai
Lin, Jie
Tian, Xia
Wu, Hui
Lu, Jiahong
Wong, Lee-Jun
Beeson, David
Zhao, Chongbo
author_facet Xi, Jianying
Yan, Chong
Liu, Wei-Wei
Qiao, Kai
Lin, Jie
Tian, Xia
Wu, Hui
Lu, Jiahong
Wong, Lee-Jun
Beeson, David
Zhao, Chongbo
author_sort Xi, Jianying
collection PubMed
description BACKGROUND: Congenital myasthenic syndrome caused by mutations in AGRN, a gene encoding a protein with a crucial function at the neuromuscular junction, is a rare disorder. There are few studies in this area. We here present two cases with novel mutations of AGRN of which we further investigated possible pathogenesis. RESULTS: Patient 1 had general limb weakness with fluctuation and deterioration in the afternoon and in hot weather. Patient 2 had early-onset weakness of lower extremities with suspected fluctuation in the early stages, which then progressed to the upper limbs. Both distal and proximal muscles were involved. Repetitive stimulation on EMG in both patients showed decrement in proximal and distal limbs. Patient 2 showed a marked response to salbutamol while Patient 1 did not. By targeted exome sequencing, two novel homozygous missense variants, p.L1176P and p.R1698C, in the SEA and LG2 domain of agrin were identified respectively. Further functional analysis revealed instability of the protein and impaired clustering of the acetylcholine receptor (AChR) by both mutations. CONCLUSIONS: The mutations identified in AGRN in our study may cause congenital myasthenic syndrome by damaging protein stability and interfering with AChR clustering. These results broaden the understandings on the phenotype, genotype and pathogenesis of this rare disorder. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13023-017-0732-z) contains supplementary material, which is available to authorized users.
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spelling pubmed-57359002017-12-21 Novel SEA and LG2 Agrin mutations causing congenital Myasthenic syndrome Xi, Jianying Yan, Chong Liu, Wei-Wei Qiao, Kai Lin, Jie Tian, Xia Wu, Hui Lu, Jiahong Wong, Lee-Jun Beeson, David Zhao, Chongbo Orphanet J Rare Dis Letter to the Editor BACKGROUND: Congenital myasthenic syndrome caused by mutations in AGRN, a gene encoding a protein with a crucial function at the neuromuscular junction, is a rare disorder. There are few studies in this area. We here present two cases with novel mutations of AGRN of which we further investigated possible pathogenesis. RESULTS: Patient 1 had general limb weakness with fluctuation and deterioration in the afternoon and in hot weather. Patient 2 had early-onset weakness of lower extremities with suspected fluctuation in the early stages, which then progressed to the upper limbs. Both distal and proximal muscles were involved. Repetitive stimulation on EMG in both patients showed decrement in proximal and distal limbs. Patient 2 showed a marked response to salbutamol while Patient 1 did not. By targeted exome sequencing, two novel homozygous missense variants, p.L1176P and p.R1698C, in the SEA and LG2 domain of agrin were identified respectively. Further functional analysis revealed instability of the protein and impaired clustering of the acetylcholine receptor (AChR) by both mutations. CONCLUSIONS: The mutations identified in AGRN in our study may cause congenital myasthenic syndrome by damaging protein stability and interfering with AChR clustering. These results broaden the understandings on the phenotype, genotype and pathogenesis of this rare disorder. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13023-017-0732-z) contains supplementary material, which is available to authorized users. BioMed Central 2017-12-19 /pmc/articles/PMC5735900/ /pubmed/29258548 http://dx.doi.org/10.1186/s13023-017-0732-z Text en © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Letter to the Editor
Xi, Jianying
Yan, Chong
Liu, Wei-Wei
Qiao, Kai
Lin, Jie
Tian, Xia
Wu, Hui
Lu, Jiahong
Wong, Lee-Jun
Beeson, David
Zhao, Chongbo
Novel SEA and LG2 Agrin mutations causing congenital Myasthenic syndrome
title Novel SEA and LG2 Agrin mutations causing congenital Myasthenic syndrome
title_full Novel SEA and LG2 Agrin mutations causing congenital Myasthenic syndrome
title_fullStr Novel SEA and LG2 Agrin mutations causing congenital Myasthenic syndrome
title_full_unstemmed Novel SEA and LG2 Agrin mutations causing congenital Myasthenic syndrome
title_short Novel SEA and LG2 Agrin mutations causing congenital Myasthenic syndrome
title_sort novel sea and lg2 agrin mutations causing congenital myasthenic syndrome
topic Letter to the Editor
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735900/
https://www.ncbi.nlm.nih.gov/pubmed/29258548
http://dx.doi.org/10.1186/s13023-017-0732-z
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