Slow-channel myasthenie syndrome caused by enhanced activation and agonist binding affinity due to mutation in the M2 domain of the ACHR α subunit

M. Milone, H. L. Wang, K. Ohno, T. Fukudome, Jerry N Pruitt, N. Bren, S. M. Sine, A. G. Engel

Research output: Contribution to journalArticle

Abstract

We describe a novel genetic and kinetic defect in a slowchannel congenital myasthénie syndrome. A 12-year-old boy had severe myasthénie symptoms since birth, 45-60% EMG decrement, repetitive compound muscle action potential, no anti-AChR antibodies, and no similarly affected relatives. He had a severe endplate myopathy causing loss of AChR, long and biexponentially decaying endplate currents, and markedly prolonged opening episodes of single AChR channels. Genetic analysis showed a heterozygous V249F mutation in the a-M2 channel pore domain in the patient and mosaicism for ctV249F in his asymptomatic father. Expression studies in HEK cells revealed prolonged channel openings, increased conductance, increased affinity for ACh, openings in the absence of ACh, and enhanced desehsitization. Neuromuscular transmission is compromised by cationic overloading, loss of AChR, partial AChR desensitization in the resting state, and depolarization block on activity from staircase summation of prolonged endplate potentials.

Original languageEnglish (US)
Number of pages1
JournalItalian Journal of Neurological Sciences
Volume18
Issue number4
StatePublished - Dec 1 1997
Externally publishedYes

Fingerprint

Mosaicism
Muscular Diseases
Fathers
Action Potentials
Anti-Idiotypic Antibodies
Parturition
Muscles
Mutation
Psychologic Desensitization

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

Cite this

Slow-channel myasthenie syndrome caused by enhanced activation and agonist binding affinity due to mutation in the M2 domain of the ACHR α subunit. / Milone, M.; Wang, H. L.; Ohno, K.; Fukudome, T.; Pruitt, Jerry N; Bren, N.; Sine, S. M.; Engel, A. G.

In: Italian Journal of Neurological Sciences, Vol. 18, No. 4, 01.12.1997.

Research output: Contribution to journalArticle

@article{fcf81a67d1984e2cb6434d3947595702,
title = "Slow-channel myasthenie syndrome caused by enhanced activation and agonist binding affinity due to mutation in the M2 domain of the ACHR α subunit",
abstract = "We describe a novel genetic and kinetic defect in a slowchannel congenital myasth{\'e}nie syndrome. A 12-year-old boy had severe myasth{\'e}nie symptoms since birth, 45-60{\%} EMG decrement, repetitive compound muscle action potential, no anti-AChR antibodies, and no similarly affected relatives. He had a severe endplate myopathy causing loss of AChR, long and biexponentially decaying endplate currents, and markedly prolonged opening episodes of single AChR channels. Genetic analysis showed a heterozygous V249F mutation in the a-M2 channel pore domain in the patient and mosaicism for ctV249F in his asymptomatic father. Expression studies in HEK cells revealed prolonged channel openings, increased conductance, increased affinity for ACh, openings in the absence of ACh, and enhanced desehsitization. Neuromuscular transmission is compromised by cationic overloading, loss of AChR, partial AChR desensitization in the resting state, and depolarization block on activity from staircase summation of prolonged endplate potentials.",
author = "M. Milone and Wang, {H. L.} and K. Ohno and T. Fukudome and Pruitt, {Jerry N} and N. Bren and Sine, {S. M.} and Engel, {A. G.}",
year = "1997",
month = "12",
day = "1",
language = "English (US)",
volume = "18",
journal = "Neurological Sciences",
issn = "1590-1874",
publisher = "Springer-Verlag Italia",
number = "4",

}

TY - JOUR

T1 - Slow-channel myasthenie syndrome caused by enhanced activation and agonist binding affinity due to mutation in the M2 domain of the ACHR α subunit

AU - Milone, M.

AU - Wang, H. L.

AU - Ohno, K.

AU - Fukudome, T.

AU - Pruitt, Jerry N

AU - Bren, N.

AU - Sine, S. M.

AU - Engel, A. G.

PY - 1997/12/1

Y1 - 1997/12/1

N2 - We describe a novel genetic and kinetic defect in a slowchannel congenital myasthénie syndrome. A 12-year-old boy had severe myasthénie symptoms since birth, 45-60% EMG decrement, repetitive compound muscle action potential, no anti-AChR antibodies, and no similarly affected relatives. He had a severe endplate myopathy causing loss of AChR, long and biexponentially decaying endplate currents, and markedly prolonged opening episodes of single AChR channels. Genetic analysis showed a heterozygous V249F mutation in the a-M2 channel pore domain in the patient and mosaicism for ctV249F in his asymptomatic father. Expression studies in HEK cells revealed prolonged channel openings, increased conductance, increased affinity for ACh, openings in the absence of ACh, and enhanced desehsitization. Neuromuscular transmission is compromised by cationic overloading, loss of AChR, partial AChR desensitization in the resting state, and depolarization block on activity from staircase summation of prolonged endplate potentials.

AB - We describe a novel genetic and kinetic defect in a slowchannel congenital myasthénie syndrome. A 12-year-old boy had severe myasthénie symptoms since birth, 45-60% EMG decrement, repetitive compound muscle action potential, no anti-AChR antibodies, and no similarly affected relatives. He had a severe endplate myopathy causing loss of AChR, long and biexponentially decaying endplate currents, and markedly prolonged opening episodes of single AChR channels. Genetic analysis showed a heterozygous V249F mutation in the a-M2 channel pore domain in the patient and mosaicism for ctV249F in his asymptomatic father. Expression studies in HEK cells revealed prolonged channel openings, increased conductance, increased affinity for ACh, openings in the absence of ACh, and enhanced desehsitization. Neuromuscular transmission is compromised by cationic overloading, loss of AChR, partial AChR desensitization in the resting state, and depolarization block on activity from staircase summation of prolonged endplate potentials.

UR - http://www.scopus.com/inward/record.url?scp=33746342176&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746342176&partnerID=8YFLogxK

M3 - Article

VL - 18

JO - Neurological Sciences

JF - Neurological Sciences

SN - 1590-1874

IS - 4

ER -