A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia.
Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic disorders affecting neuromuscular transmission. The agrin/muscle-specific kinase (MuSK) pathway is critical for proper development and maintenance of the neuromuscular junction (NMJ). We report here an Iranian patient in who...
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doaj-e68477a48eb441748de3168741d933102020-11-25T01:45:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0181e5382610.1371/journal.pone.0053826A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia.Asma Ben AmmarPayam SoltanzadehStéphanie BauchéPascale RichardEvelyne GoillotRuth HerbstKaren GaudonCaroline HuzéLaurent SchaefferYuji YamanashiOsamu HiguchiAntoine TalyJeanine KoenigJean-Paul LeroyFayçal HentatiHossein NajmabadiKimia KahriziManouchehr IlkhaniMichel FardeauBruno EymardDaniel HantaïCongenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic disorders affecting neuromuscular transmission. The agrin/muscle-specific kinase (MuSK) pathway is critical for proper development and maintenance of the neuromuscular junction (NMJ). We report here an Iranian patient in whom CMS was diagnosed since he presented with congenital and fluctuating bilateral symmetric ptosis, upward gaze palsy and slowly progressive muscle weakness leading to loss of ambulation. Genetic analysis of the patient revealed a homozygous missense mutation c.2503A>G in the coding sequence of MUSK leading to the p.Met835Val substitution. The mutation was inherited from the two parents who were heterozygous according to the notion of consanguinity. Immunocytochemical and electron microscopy studies of biopsied deltoid muscle showed dramatic changes in pre- and post-synaptic elements of the NMJs. These changes induced a process of denervation/reinnervation in native NMJs and the formation, by an adaptive mechanism, of newly formed and ectopic NMJs. Aberrant axonal outgrowth, decreased nerve terminal ramification and nodal axonal sprouting were also noted. In vivo electroporation of the mutated MuSK in a mouse model showed disorganized NMJs and aberrant axonal growth reproducing a phenotype similar to that observed in the patient's biopsy specimen. In vitro experiments showed that the mutation alters agrin-dependent acetylcholine receptor aggregation, causes a constitutive activation of MuSK and a decrease in its agrin- and Dok-7-dependent phosphorylation.http://europepmc.org/articles/PMC3541344?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Asma Ben Ammar Payam Soltanzadeh Stéphanie Bauché Pascale Richard Evelyne Goillot Ruth Herbst Karen Gaudon Caroline Huzé Laurent Schaeffer Yuji Yamanashi Osamu Higuchi Antoine Taly Jeanine Koenig Jean-Paul Leroy Fayçal Hentati Hossein Najmabadi Kimia Kahrizi Manouchehr Ilkhani Michel Fardeau Bruno Eymard Daniel Hantaï |
spellingShingle |
Asma Ben Ammar Payam Soltanzadeh Stéphanie Bauché Pascale Richard Evelyne Goillot Ruth Herbst Karen Gaudon Caroline Huzé Laurent Schaeffer Yuji Yamanashi Osamu Higuchi Antoine Taly Jeanine Koenig Jean-Paul Leroy Fayçal Hentati Hossein Najmabadi Kimia Kahrizi Manouchehr Ilkhani Michel Fardeau Bruno Eymard Daniel Hantaï A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia. PLoS ONE |
author_facet |
Asma Ben Ammar Payam Soltanzadeh Stéphanie Bauché Pascale Richard Evelyne Goillot Ruth Herbst Karen Gaudon Caroline Huzé Laurent Schaeffer Yuji Yamanashi Osamu Higuchi Antoine Taly Jeanine Koenig Jean-Paul Leroy Fayçal Hentati Hossein Najmabadi Kimia Kahrizi Manouchehr Ilkhani Michel Fardeau Bruno Eymard Daniel Hantaï |
author_sort |
Asma Ben Ammar |
title |
A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia. |
title_short |
A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia. |
title_full |
A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia. |
title_fullStr |
A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia. |
title_full_unstemmed |
A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia. |
title_sort |
mutation causes musk reduced sensitivity to agrin and congenital myasthenia. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2013-01-01 |
description |
Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic disorders affecting neuromuscular transmission. The agrin/muscle-specific kinase (MuSK) pathway is critical for proper development and maintenance of the neuromuscular junction (NMJ). We report here an Iranian patient in whom CMS was diagnosed since he presented with congenital and fluctuating bilateral symmetric ptosis, upward gaze palsy and slowly progressive muscle weakness leading to loss of ambulation. Genetic analysis of the patient revealed a homozygous missense mutation c.2503A>G in the coding sequence of MUSK leading to the p.Met835Val substitution. The mutation was inherited from the two parents who were heterozygous according to the notion of consanguinity. Immunocytochemical and electron microscopy studies of biopsied deltoid muscle showed dramatic changes in pre- and post-synaptic elements of the NMJs. These changes induced a process of denervation/reinnervation in native NMJs and the formation, by an adaptive mechanism, of newly formed and ectopic NMJs. Aberrant axonal outgrowth, decreased nerve terminal ramification and nodal axonal sprouting were also noted. In vivo electroporation of the mutated MuSK in a mouse model showed disorganized NMJs and aberrant axonal growth reproducing a phenotype similar to that observed in the patient's biopsy specimen. In vitro experiments showed that the mutation alters agrin-dependent acetylcholine receptor aggregation, causes a constitutive activation of MuSK and a decrease in its agrin- and Dok-7-dependent phosphorylation. |
url |
http://europepmc.org/articles/PMC3541344?pdf=render |
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