PMID- 23326516
OWN - NLM
STAT- MEDLINE
DCOM- 20130719
LR  - 20220129
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 1
DP  - 2013
TI  - A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia.
PG  - e53826
LID - 10.1371/journal.pone.0053826 [doi]
LID - e53826
AB  - 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.
FAU - Ben Ammar, Asma
AU  - Ben Ammar A
AD  - Inserm, UMRS 975, UPMC, Institut du Cerveau et de la Moelle epiniere, Groupe 
      Hospitalier Pitie-Salpetriere, Paris, France.
FAU - Soltanzadeh, Payam
AU  - Soltanzadeh P
FAU - Bauche, Stephanie
AU  - Bauche S
FAU - Richard, Pascale
AU  - Richard P
FAU - Goillot, Evelyne
AU  - Goillot E
FAU - Herbst, Ruth
AU  - Herbst R
FAU - Gaudon, Karen
AU  - Gaudon K
FAU - Huze, Caroline
AU  - Huze C
FAU - Schaeffer, Laurent
AU  - Schaeffer L
FAU - Yamanashi, Yuji
AU  - Yamanashi Y
FAU - Higuchi, Osamu
AU  - Higuchi O
FAU - Taly, Antoine
AU  - Taly A
FAU - Koenig, Jeanine
AU  - Koenig J
FAU - Leroy, Jean-Paul
AU  - Leroy JP
FAU - Hentati, Faycal
AU  - Hentati F
FAU - Najmabadi, Hossein
AU  - Najmabadi H
FAU - Kahrizi, Kimia
AU  - Kahrizi K
FAU - Ilkhani, Manouchehr
AU  - Ilkhani M
FAU - Fardeau, Michel
AU  - Fardeau M
FAU - Eymard, Bruno
AU  - Eymard B
FAU - Hantai, Daniel
AU  - Hantai D
LA  - eng
GR  - P 21667/FWF_/Austrian Science Fund FWF/Austria
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130109
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Agrin)
RN  - 0 (DOK7 protein, human)
RN  - 0 (Muscle Proteins)
RN  - 0 (Receptors, Cholinergic)
RN  - 0 (Receptors, Growth Factor)
RN  - 0 (agrin receptor)
RN  - EC 2.7.10.1 (MUSK protein, human)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
EIN - PLoS One. 2013;8(9). doi: 10.1371/annotation/3ff2b918-c83c-4c6f-a2e2-4d91294ec92f
MH  - Agrin/metabolism
MH  - Animals
MH  - Child
MH  - HEK293 Cells
MH  - Humans
MH  - Male
MH  - Mice
MH  - Muscle Proteins/genetics/metabolism
MH  - *Muscle Weakness/genetics/metabolism/physiopathology
MH  - *Muscle, Skeletal/innervation/physiopathology
MH  - Mutation, Missense
MH  - *Myasthenic Syndromes, Congenital/genetics/metabolism/physiopathology
MH  - *Neuromuscular Junction/genetics/metabolism/physiopathology
MH  - Receptor Protein-Tyrosine Kinases/*genetics/metabolism
MH  - Receptors, Cholinergic/*genetics/metabolism
MH  - Receptors, Growth Factor/genetics/metabolism
MH  - Signal Transduction
MH  - Synaptic Transmission/genetics
PMC - PMC3541344
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/01/18 06:00
MHDA- 2013/07/20 06:00
PMCR- 2013/01/09
CRDT- 2013/01/18 06:00
PHST- 2012/05/14 00:00 [received]
PHST- 2012/12/05 00:00 [accepted]
PHST- 2013/01/18 06:00 [entrez]
PHST- 2013/01/18 06:00 [pubmed]
PHST- 2013/07/20 06:00 [medline]
PHST- 2013/01/09 00:00 [pmc-release]
AID - PONE-D-12-13918 [pii]
AID - 10.1371/journal.pone.0053826 [doi]
PST - ppublish
SO  - PLoS One. 2013;8(1):e53826. doi: 10.1371/journal.pone.0053826. Epub 2013 Jan 9.