Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor ε subunit

Kinji Ohno, Hai Long Wang, Margherita Milone, Nina Bren, Joan M. Brengman, Satoshi Nakano, Polly Quiram, Jerry N. Pruitt, Steven M Sine, Andrew G Engel

Research output: Contribution to journalArticle

193 Citations (Scopus)

Abstract

We describe the genetic and kinetic defects for a low-affinity fast channel disease of the acetylcholine receptor (AChR) that causes a myasthenic syndrome. In two unrelated patients with very small miniature end plate (EP) potentials, but with normal EP AChR density and normal EP ultrastructure, patch-clamp studies demonstrated infrequent AChR channel events, diminished channel reopenings during ACh occupancy, and resistance to desensitization by ACh. Each patient had two heteroallelic AChR ε subunit gene mutations: a common εP121L mutation, a signal peptide mutation (εG-8R) (patient 1), and a glycosylation consensus site mutation (εS143L) (patient 2). AChR expression in HEK fibroblasts was normal with εP121L but was markedly reduced with the other mutations. Therefore, εP121L defines the clinical phenotype. Studies of the engineered EP121L AChR revealed a markedly decreased rate of channel opening, little change in affinity of the resting state for ACh, but reduced affinity of the open channel and desensitized states.

Original languageEnglish (US)
Pages (from-to)157-170
Number of pages14
JournalNeuron
Volume17
Issue number1
DOIs
StatePublished - Jul 1996

Fingerprint

Congenital Myasthenic Syndromes
Cholinergic Receptors
Mutation
Miniature Postsynaptic Potentials
Muscle Weakness
Protein Sorting Signals
Glycosylation
Fibroblasts
Phenotype

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor ε subunit. / Ohno, Kinji; Wang, Hai Long; Milone, Margherita; Bren, Nina; Brengman, Joan M.; Nakano, Satoshi; Quiram, Polly; Pruitt, Jerry N.; Sine, Steven M; Engel, Andrew G.

In: Neuron, Vol. 17, No. 1, 07.1996, p. 157-170.

Research output: Contribution to journalArticle

Ohno, Kinji ; Wang, Hai Long ; Milone, Margherita ; Bren, Nina ; Brengman, Joan M. ; Nakano, Satoshi ; Quiram, Polly ; Pruitt, Jerry N. ; Sine, Steven M ; Engel, Andrew G. / Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor ε subunit. In: Neuron. 1996 ; Vol. 17, No. 1. pp. 157-170.
@article{c92bbc4ff93d4915b798f19a52650d5e,
title = "Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor ε subunit",
abstract = "We describe the genetic and kinetic defects for a low-affinity fast channel disease of the acetylcholine receptor (AChR) that causes a myasthenic syndrome. In two unrelated patients with very small miniature end plate (EP) potentials, but with normal EP AChR density and normal EP ultrastructure, patch-clamp studies demonstrated infrequent AChR channel events, diminished channel reopenings during ACh occupancy, and resistance to desensitization by ACh. Each patient had two heteroallelic AChR ε subunit gene mutations: a common εP121L mutation, a signal peptide mutation (εG-8R) (patient 1), and a glycosylation consensus site mutation (εS143L) (patient 2). AChR expression in HEK fibroblasts was normal with εP121L but was markedly reduced with the other mutations. Therefore, εP121L defines the clinical phenotype. Studies of the engineered EP121L AChR revealed a markedly decreased rate of channel opening, little change in affinity of the resting state for ACh, but reduced affinity of the open channel and desensitized states.",
author = "Kinji Ohno and Wang, {Hai Long} and Margherita Milone and Nina Bren and Brengman, {Joan M.} and Satoshi Nakano and Polly Quiram and Pruitt, {Jerry N.} and Sine, {Steven M} and Engel, {Andrew G}",
year = "1996",
month = "7",
doi = "10.1016/S0896-6273(00)80289-5",
language = "English (US)",
volume = "17",
pages = "157--170",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor ε subunit

AU - Ohno, Kinji

AU - Wang, Hai Long

AU - Milone, Margherita

AU - Bren, Nina

AU - Brengman, Joan M.

AU - Nakano, Satoshi

AU - Quiram, Polly

AU - Pruitt, Jerry N.

AU - Sine, Steven M

AU - Engel, Andrew G

PY - 1996/7

Y1 - 1996/7

N2 - We describe the genetic and kinetic defects for a low-affinity fast channel disease of the acetylcholine receptor (AChR) that causes a myasthenic syndrome. In two unrelated patients with very small miniature end plate (EP) potentials, but with normal EP AChR density and normal EP ultrastructure, patch-clamp studies demonstrated infrequent AChR channel events, diminished channel reopenings during ACh occupancy, and resistance to desensitization by ACh. Each patient had two heteroallelic AChR ε subunit gene mutations: a common εP121L mutation, a signal peptide mutation (εG-8R) (patient 1), and a glycosylation consensus site mutation (εS143L) (patient 2). AChR expression in HEK fibroblasts was normal with εP121L but was markedly reduced with the other mutations. Therefore, εP121L defines the clinical phenotype. Studies of the engineered EP121L AChR revealed a markedly decreased rate of channel opening, little change in affinity of the resting state for ACh, but reduced affinity of the open channel and desensitized states.

AB - We describe the genetic and kinetic defects for a low-affinity fast channel disease of the acetylcholine receptor (AChR) that causes a myasthenic syndrome. In two unrelated patients with very small miniature end plate (EP) potentials, but with normal EP AChR density and normal EP ultrastructure, patch-clamp studies demonstrated infrequent AChR channel events, diminished channel reopenings during ACh occupancy, and resistance to desensitization by ACh. Each patient had two heteroallelic AChR ε subunit gene mutations: a common εP121L mutation, a signal peptide mutation (εG-8R) (patient 1), and a glycosylation consensus site mutation (εS143L) (patient 2). AChR expression in HEK fibroblasts was normal with εP121L but was markedly reduced with the other mutations. Therefore, εP121L defines the clinical phenotype. Studies of the engineered EP121L AChR revealed a markedly decreased rate of channel opening, little change in affinity of the resting state for ACh, but reduced affinity of the open channel and desensitized states.

UR - http://www.scopus.com/inward/record.url?scp=15844429136&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=15844429136&partnerID=8YFLogxK

U2 - 10.1016/S0896-6273(00)80289-5

DO - 10.1016/S0896-6273(00)80289-5

M3 - Article

VL - 17

SP - 157

EP - 170

JO - Neuron

JF - Neuron

SN - 0896-6273

IS - 1

ER -