 |
Next Article 
Volume 17, Number 15,
Issue of August 1, 1997
pp. 5651-5665
Copyright ©1997 Society for Neuroscience
Slow-Channel Myasthenic Syndrome Caused By Enhanced Activation,
Desensitization, and Agonist Binding Affinity Attributable to
Mutation in the M2 Domain of the Acetylcholine Receptor  Subunit
Received Feb. 6, 1997; revised April 10, 1997; accepted May 9, 1997.
Margherita Milone1,
Hai-Long Wang2,
Kinji Ohno1,
Takayasu Fukudome1,
J. Ned Pruitt1,
Nina Bren2,
Steven M. Sine2, and
Andrew G. Engel1
1 Muscle Research Laboratory, Department of Neurology,
and 2 Receptor Biology Laboratory, Department of Physiology
and Biophysics, Mayo Foundation, Rochester, Minnesota 55905
We describe a novel genetic and kinetic defect in a
slow-channel congenital myasthenic syndrome. The severely disabled
propositus has advanced endplate myopathy, prolonged and
biexponentially decaying endplate currents, and prolonged acetylcholine
receptor (AChR) channel openings. Genetic analysis reveals the
heterozygous mutation  V249F in the propositus and mosaicism for
V249F in the asymptomatic father. Unlike mutations described
previously in the M2 transmembrane domain, V249F is located
N-terminal to the conserved leucines and is not predicted to face the
channel lumen. Expression of the V249F AChR in HEK fibroblasts
demonstrates increased channel openings in the absence of ACh,
prolonged openings in its presence, enhanced steady-state
desensitization, and nanomolar rather than micromolar affinity of one
of the two binding sites in the resting activatable state. Thus,
neuromuscular transmission is compromised because cationic overloading
leads to degenerating junctional folds and loss of AChR, because an
increased fraction of AChR is desensitized in the resting state, and
because physiological rates of stimulation elicit additional
desensitization and depolarization block of transmission.
Key words:
slow-channel congenital myasthenic syndrome;
neuromuscular transmission;
endplate myopathy;
acetylcholine receptor
subunit gene;
mutation analysis;
single-channel recording;
desensitization;
agonist binding affinity
This article has been cited by other articles:
|
|
|
|
 
R. Lape, P. Krashia, D. Colquhoun, and L. G. Sivilotti
Agonist and blocking actions of choline and tetramethylammonium on human muscle acetylcholine receptors
J. Physiol.,
November 1, 2009;
587(21):
5045 - 5072.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Purohit and A. Auerbach
Unliganded gating of acetylcholine receptor channels
PNAS,
January 6, 2009;
106(1):
115 - 120.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Mihaylova, J. S. Muller, J. J. Vilchez, M. A. Salih, M. M. Kabiraj, A. D'Amico, E. Bertini, J. Wolfle, F. Schreiner, G. Kurlemann, et al.
Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes
Brain,
March 1, 2008;
131(3):
747 - 759.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Mukhtasimova and S. M. Sine
An Intersubunit Trigger of Channel Gating in the Muscle Nicotinic Receptor
J. Neurosci.,
April 11, 2007;
27(15):
4110 - 4119.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Fucile, A. Sucapane, F. Grassi, F. Eusebi, and A. G. Engel
The human adult subtype ACh receptor channel has high Ca2+ permeability and predisposes to endplate Ca2+ overloading
J. Physiol.,
May 15, 2006;
573(1):
35 - 43.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Milone, T. Fukuda, X. M. Shen, A. Tsujino, J. Brengman, and A. G. Engel
Novel congenital myasthenic syndromes associated with defects in quantal release
Neurology,
April 25, 2006;
66(8):
1223 - 1229.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Rayes, G. Spitzmaul, S. M. Sine, and C. Bouzat
Single-Channel Kinetic Analysis of Chimeric {alpha}7-5HT3A Receptors
Mol. Pharmacol.,
November 1, 2005;
68(5):
1475 - 1483.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Shelley and D. Colquhoun
A human congenital myasthenia-causing mutation ({varepsilon}L78P) of the muscle nicotinic acetylcholine receptor with unusual single channel properties
J. Physiol.,
April 15, 2005;
564(2):
377 - 396.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Lefebvre, F. Ono, C. Puglielli, G. Seidner, C. Franzini-Armstrong, P. Brehm, and M. Granato
Increased neuromuscular activity causes axonal defects and muscular degeneration
Development,
June 1, 2004;
131(11):
2605 - 2618.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Webster, M. Brydson, R. Croxen, J. Newsom-Davis, A. Vincent, and D. Beeson
Mutation in the AChR ion channel gate underlies a fast channel congenital myasthenic syndrome
Neurology,
April 13, 2004;
62(7):
1090 - 1096.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C J Hatton, C Shelley, M Brydson, D Beeson, and D Colquhoun
Properties of the human muscle nicotinic receptor, and of the slow-channel myasthenic syndrome mutant {varepsilon}L221F, inferred from maximum likelihood fits
J. Physiol.,
March 15, 2003;
547(3):
729 - 760.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D Colquhoun, C J Hatton, and A G Hawkes
The quality of maximum likelihood estimates of ion channel rate constants
J. Physiol.,
March 15, 2003;
547(3):
699 - 728.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Sine, X.-M. Shen, H.-L. Wang, K. Ohno, W.-Y. Lee, A. Tsujino, J. Brengmann, N. Bren, J. Vajsar, and A. G. Engel
Naturally Occurring Mutations at the Acetylcholine Receptor Binding Site Independently Alter ACh Binding and Channel Gating
J. Gen. Physiol.,
September 30, 2002;
120(4):
483 - 496.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Gomez, R. A. Maselli, J. Groshong, R. Zayas, R. L. Wollmann, T. Cens, and P. Charnet
Active Calcium Accumulation Underlies Severe Weakness in a Panel of Mice with Slow-Channel Syndrome
J. Neurosci.,
August 1, 2002;
22(15):
6447 - 6457.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Croxen, C. Hatton, C. Shelley, M. Brydson, G. Chauplannaz, H. Oosterhuis, A. Vincent, J. Newsom-Davis, D. Colquhoun, and D. Beeson
Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes
Neurology,
July 23, 2002;
59(2):
162 - 168.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Grosman and A. Auerbach
The dissociation of acetylcholine from open nicotinic receptor channels
PNAS,
November 20, 2001;
98(24):
14102 - 14107.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Grosman and A. Auerbach
Kinetic, Mechanistic, and Structural Aspects of Unliganded Gating of Acetylcholine Receptor Channels: A Single-Channel Study of Second Transmembrane Segment 12' Mutants
J. Gen. Physiol.,
May 1, 2000;
115(5):
621 - 635.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Abicht, R. Stucka, V. Karcagi, A. Herczegfalvi, R. Horvath, W. Mortier, U. Schara, V. Ramaekers, W. Jost, J. Brunner, et al.
A common mutation ({epsilon}1267delG) in congenital myasthenic patients of Gypsy ethnic origin
Neurology,
October 22, 1999;
53(7):
1564 - 1564.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Middleton, K. Ohno, K. Christodoulou, J. Brengman, M. Milone, V. Neocleous, P. Serdaroglu, F. Deymeer, C. Ozdemir, A. Mubaidin, et al.
Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor {epsilon}-subunit gene
Neurology,
September 1, 1999;
53(5):
1076 - 1076.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
M. Zhou, A. G. Engel, and A. Auerbach
Serum choline activates mutant acetylcholine receptors that cause slow channel congenital myasthenic syndromes
PNAS,
August 31, 1999;
96(18):
10466 - 10471.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. G. Engel, K. Ohno, and S. M. Sine
Congenital Myasthenic Syndromes: Recent Advances
Arch Neurol,
February 1, 1999;
56(2):
163 - 167.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. North
NEW PERSPECTIVES IN PEDIATRIC NEUROMUSCULAR DISORDERS Hotel Intercontinental Sydney, Sydney, Australia, August 28, 1998
J Child Neurol,
January 1, 1999;
14(1):
26 - 57.
[PDF]
|
|
|
|
|
|
|
A. Auerbach and G. Akk
Desensitization of Mouse Nicotinic Acetylcholine Receptor Channels: A Two-Gate Mechanism
J. Gen. Physiol.,
August 1, 1998;
112(2):
181 - 197.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. G. Engel, K. Ohno, H.-L. Wang, M. Milone, and S. M. Sine
REVIEW {blacksquare} : Molecular Basis of Congenital Myasthenic Syndromes: Mutations in the Acetylcholine Receptor
Neuroscientist,
May 1, 1998;
4(3):
185 - 194.
[Abstract]
[PDF]
|
|
|
|
|
|
|
G. G. Wilson and A. Karlin
Inaugural Article: Acetylcholine receptor channel structure in the resting, open, and desensitized states probed with the substituted-cysteine-accessibility method
PNAS,
January 30, 2001;
98(3):
1241 - 1248.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
