A leucine‐to‐phenylalanine substitution in the acetylcholine receptor ion channel in a family with the slow‐channel syndrome

Gómez, Christopher M.; Gammack, Jason

doi:10.1212/wnl.45.5.982

Cited by 61 publications

(33 citation statements)

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“…Electron microscope observations reveal that the syndrome is accompanied by various defects in the postsynaptic junctional folds (Engel et al 1992. Alleles occur in the ␣, b, and e subunits (Gomez & Gammack 1995;Gomez et al 1996bGomez et al , 1998. Several slow-channel alleles produce hypersensitive receptors, with dose-response relations for acetylcholine shifted to the left.…”

Section: Gating Changes: Constitutive Activationmentioning

confidence: 99%

Gain of Function Mutants: Ion Channels and G Protein-Coupled Receptors

Lester

Karschin

2000

Annu. Rev. Neurosci.

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Many ion channels and receptors display striking phenotypes for gainof-function mutations but milder phenotypes for null mutations. Gain of molecular function can have several mechanistic bases: selectivity changes, gating changes including constitutive activation and slowed inactivation, elimination of a subunit that enhances inactivation, decreased drug sensitivity, changes in regulation or trafficking of the channel, or induction of apoptosis. Decreased firing frequency can occur via increased function of K ‫ם‬ or Cl ‫מ‬ channels. Channel mutants also cause gain-of-function syndromes at the cellular and circuit level; of these syndromes, the cardiac long-QT syndromes are explained in a more straightforward way than are the epilepsies. G proteincoupled receptors are also affected by activating mutations.

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Section: Gating Changes: Constitutive Activationmentioning

confidence: 99%

Gain of Function Mutants: Ion Channels and G Protein-Coupled Receptors

Lester

Karschin

2000

Annu. Rev. Neurosci.

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“…The slow-channel congenital myasthenic syndrome (SCCMS) is a dominantly inherited disorder of neuromuscular transmission in which electrophysiological features of abnormal acetylcholine receptor (AChR) ion channel kinetics have been associated with point mutations in the genes encoding the subunits of the AChR (Engel et al, 1982;Oosterhuis et al, 1987;Gomez and Gammack, 1995;Sine et al, 1995;Ohno et al, 1995;Engel et al, 1996;Gomez et al, 1996b). It is the first of what may be a family of disorders of altered or exaggerated synaptic receptor function that underlie poorly understood neurodegenerative, convulsive, or psychiatric disorders (Shiang et al, 1993;Steinlein et al, 1995;Treinin and Chalfie, 1995;Ophoff et al, 1996).…”

Section: Abstract: Transgenic Mice; Neuromuscular Junction; Slowchanmentioning

confidence: 99%

“…Recently we reported the occurrence of a mutation, ⑀L269F (Gomez and Gammack, 1995), in the sequence encoding the channel-lining domain of the ⑀ subunit in the three affected members of a kindred with SCCMS. To investigate the role of this mutant subunit in the pathogenesis of the constellation of electrophysiological and pathological features constituting the SCCMS, we studied its properties in vitro and in vivo.…”

Section: Abstract: Transgenic Mice; Neuromuscular Junction; Slowchanmentioning

confidence: 99%

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Slow-Channel Transgenic Mice: A Model of Postsynaptic Organellar Degeneration at the Neuromuscular Junction

Gómez

Maselli²,

Gundeck³

et al. 1997

J. Neurosci.

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The slow-channel congenital myasthenic syndrome (SCCMS) is a dominantly inherited disorder of neuromuscular transmission characterized by delayed closure of the skeletal muscle acetylcholine receptor (AChR) ion channel and degeneration of the neuromuscular junction. The identification of a series of AChR subunit mutations in the SCCMS supports the hypothesis that the altered kinetics of the endplate currents in this disease are attributable to inherited abnormalities of the AChR. To investigate the role of these mutant AChR subunits in the development of the synaptic degeneration seen in the SCCMS, we have studied the properties of the AChR mutation, ⑀L269F, found in a family with SCCMS, using both in vitro and in vivo expression systems. The mutation causes a sixfold increase in the open time of AChRs expressed in vitro, similar to the phenotype of other reported mutants. Transgenic mice expressing this mutant develop a syndrome that is highly reminiscent of the SCCMS. Mice have fatigability of limb muscles, electrophysiological evidence of slow AChR ion channels, and defective neuromuscular transmission. Pathologically, the motor endplates show focal accumulation of calcium and striking ultrastructural changes, including enlargement and degeneration of the subsynaptic mitochondria and nuclei. These findings clearly demonstrate the role of this mutation in the spectrum of abnormalities associated with the SCCMS and point to the subsynaptic organelles as principal targets in this disease. These transgenic mice provide a useful model for the study of excitotoxic synaptic degeneration.

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“…neuromuscular | quinidine | nicotinic receptor T he developmental switch from the embryonic αβδγ to the adult αβδε muscle ACh receptor isoform occurs in every vertebrate species studied to date (1)(2)(3). Certain mutations in ε result in the lifelong myasthenic disorder slow-channel syndrome (SCS) (4)(5)(6), whereas mutations in the γ subunit are restricted to Escobar syndrome, characterized by improvement in neuromuscular performance during development (7,8). All documented cases of Escobar syndrome are thought to represent ACh receptor nulls that are corrected by the developmental appearance of the wild-type ε subunit, thereby rescuing receptor expression (9).…”

mentioning

confidence: 99%

Zebrafish model for congenital myasthenic syndrome reveals mechanisms causal to developmental recovery

Walogorsky

Mongeon

Hua

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in muscle ACh receptors cause slow-channel syndrome (SCS) and Escobar syndrome, two forms of congenital myasthenia. SCS is a dominant disorder with mutations reported for all receptor subunits except γ. Escobar syndrome is distinct, with mutations located exclusively in γ, and characterized by developmental improvement of muscle function. The zebrafish mutant line, twister , models SCS in terms of a dominant mutation in the α subunit (α twi ) but shows the behavioral improvement associated with Escobar syndrome. Here, we present a unique electrophysiological study into developmental improvement for a myasthenic syndrome. The embryonic α twi βδγ receptor isoform produces slowly decaying synaptic currents typical of SCS that transit to a much faster decay upon the appearance of adult ε, despite the α twi mutation. Thus, the continued expression of α twi into adulthood is tolerated because of the ε expression and associated recovery, raising the likelihood of unappreciated myasthenic cases that benefit from the γ−ε switch.

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A leucine‐to‐phenylalanine substitution in the acetylcholine receptor ion channel in a family with the slow‐channel syndrome

Cited by 61 publications

References 0 publications

Gain of Function Mutants: Ion Channels and G Protein-Coupled Receptors

Gain of Function Mutants: Ion Channels and G Protein-Coupled Receptors

Slow-Channel Transgenic Mice: A Model of Postsynaptic Organellar Degeneration at the Neuromuscular Junction

Zebrafish model for congenital myasthenic syndrome reveals mechanisms causal to developmental recovery

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