Abstract
We describe a severe congenital myasthenic syndrome (CMS) caused by two missense mutations in the gene encoding the muscle specific receptor tyrosine kinase (MUSK). The identified MUSK mutations M605I and A727V are both located in the kinase domain of MuSK. Intracellular microelectrode recordings and microscopy studies of the neuromuscular junction conducted in an anconeus muscle biopsy revealed decreased miniature endplate potential amplitudes, reduced endplate size and simplification of secondary synaptic folds, which were consistent with postsynaptic deficit. The study also showed a striking reduction of the endplate potential quantal content, consistent with additional presynaptic failure. Expression studies inMuSKdeficientmyotubes revealed that A727V,which is located within the catalytic loop of theenzyme, causedsevere impairment of agrindependent MuSK phosphorylation, aggregation of acetylcholine receptors (AChRs) and interaction of MuSK with Dok-7, an essential intracellular binding protein of MuSK. In contrast, M605I, resulted in only moderate impairment of agrin-dependent MuSK phosphorylation, aggregation of AChRs and interaction of MuSK with Dok-7. There was no impairment of interaction of mutants with either the low-density lipoprotein receptorrelated protein, Lrp4 (a co-receptor of agrin) or with the mammalian homolog of the Drosophila tumorous imaginal discs (Tid1). Our findings demonstrate that missense mutations in MUSK can result in a severe form of CMS and indicate that the inability of MuSK mutants to interact with Dok-7, but not with Lrp4 or Tid1, is a major determinant of the pathogenesis of the CMS caused by MUSK mutations.
| Original language | English (US) |
|---|---|
| Article number | ddq110 |
| Pages (from-to) | 2370-2379 |
| Number of pages | 10 |
| Journal | Human Molecular Genetics |
| Volume | 19 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jun 15 2010 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
- Molecular Biology
Cite this
Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction. / Maselli, Ricardo A; Arredondo, Juan; Cagney, Órla; Ng, Jarae J.; Anderson, Jennifer A.; Williams, Colette; Gerke, Bae J.; Soliven, Betty; Wollmann, Robert L.
In: Human Molecular Genetics, Vol. 19, No. 12, ddq110, 15.06.2010, p. 2370-2379.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction
AU - Maselli, Ricardo A
AU - Arredondo, Juan
AU - Cagney, Órla
AU - Ng, Jarae J.
AU - Anderson, Jennifer A.
AU - Williams, Colette
AU - Gerke, Bae J.
AU - Soliven, Betty
AU - Wollmann, Robert L.
PY - 2010/6/15
Y1 - 2010/6/15
N2 - We describe a severe congenital myasthenic syndrome (CMS) caused by two missense mutations in the gene encoding the muscle specific receptor tyrosine kinase (MUSK). The identified MUSK mutations M605I and A727V are both located in the kinase domain of MuSK. Intracellular microelectrode recordings and microscopy studies of the neuromuscular junction conducted in an anconeus muscle biopsy revealed decreased miniature endplate potential amplitudes, reduced endplate size and simplification of secondary synaptic folds, which were consistent with postsynaptic deficit. The study also showed a striking reduction of the endplate potential quantal content, consistent with additional presynaptic failure. Expression studies inMuSKdeficientmyotubes revealed that A727V,which is located within the catalytic loop of theenzyme, causedsevere impairment of agrindependent MuSK phosphorylation, aggregation of acetylcholine receptors (AChRs) and interaction of MuSK with Dok-7, an essential intracellular binding protein of MuSK. In contrast, M605I, resulted in only moderate impairment of agrin-dependent MuSK phosphorylation, aggregation of AChRs and interaction of MuSK with Dok-7. There was no impairment of interaction of mutants with either the low-density lipoprotein receptorrelated protein, Lrp4 (a co-receptor of agrin) or with the mammalian homolog of the Drosophila tumorous imaginal discs (Tid1). Our findings demonstrate that missense mutations in MUSK can result in a severe form of CMS and indicate that the inability of MuSK mutants to interact with Dok-7, but not with Lrp4 or Tid1, is a major determinant of the pathogenesis of the CMS caused by MUSK mutations.
AB - We describe a severe congenital myasthenic syndrome (CMS) caused by two missense mutations in the gene encoding the muscle specific receptor tyrosine kinase (MUSK). The identified MUSK mutations M605I and A727V are both located in the kinase domain of MuSK. Intracellular microelectrode recordings and microscopy studies of the neuromuscular junction conducted in an anconeus muscle biopsy revealed decreased miniature endplate potential amplitudes, reduced endplate size and simplification of secondary synaptic folds, which were consistent with postsynaptic deficit. The study also showed a striking reduction of the endplate potential quantal content, consistent with additional presynaptic failure. Expression studies inMuSKdeficientmyotubes revealed that A727V,which is located within the catalytic loop of theenzyme, causedsevere impairment of agrindependent MuSK phosphorylation, aggregation of acetylcholine receptors (AChRs) and interaction of MuSK with Dok-7, an essential intracellular binding protein of MuSK. In contrast, M605I, resulted in only moderate impairment of agrin-dependent MuSK phosphorylation, aggregation of AChRs and interaction of MuSK with Dok-7. There was no impairment of interaction of mutants with either the low-density lipoprotein receptorrelated protein, Lrp4 (a co-receptor of agrin) or with the mammalian homolog of the Drosophila tumorous imaginal discs (Tid1). Our findings demonstrate that missense mutations in MUSK can result in a severe form of CMS and indicate that the inability of MuSK mutants to interact with Dok-7, but not with Lrp4 or Tid1, is a major determinant of the pathogenesis of the CMS caused by MUSK mutations.
UR - http://www.scopus.com/inward/record.url?scp=77955293046&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77955293046&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddq110
DO - 10.1093/hmg/ddq110
M3 - Article
C2 - 20371544
AN - SCOPUS:77955293046
VL - 19
SP - 2370
EP - 2379
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 12
M1 - ddq110
ER -