Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5

Bendahhou, Saı̈d; Cummins, Theodore R.; Kula, Roger W.; Fu, Ying Hui; Ptáček, Louis J.

doi:10.1212/wnl.58.8.1266

Cited by 67 publications

(75 citation statements)

References 31 publications

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“…The functional consequences of the I693T and T704M mutations on hNa v 1.4 have been characterized after expression in HEK293 cells (Plassart-Schiess et al, 1998;Hayward et al, 1999;Bendahhou et al, 2002) and are similar to the effects of the I848T mutation on hNa v 1.7. All of these mutations shift the voltage dependence of activation in a hyperpolarizing direction.…”

Section: Discussionmentioning

confidence: 88%

Electrophysiological Properties of Mutant Na_v1.7 Sodium Channels in a Painful Inherited Neuropathy

Cummins¹,

Dib‐Hajj²,

Waxman³

2004

J. Neurosci.

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363

289

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Although the physiological basis of erythermalgia, an autosomal dominant painful neuropathy characterized by redness of the skin and intermittent burning sensation of extremities, is not known, two mutations of Na v 1.7, a sodium channel that produces a tetrodotoxinsensitive, fast-inactivating current that is preferentially expressed in dorsal root ganglia (DRG) and sympathetic ganglia neurons, have recently been identified in patients with primary erythermalgia. Na v 1.7 is preferentially expressed in small-diameter DRG neurons, most of which are nociceptors, and is characterized by slow recovery from inactivation and by slow closed-state inactivation that results in relatively large responses to small, subthreshold depolarizations. Here we show that these mutations in Na v 1.7 produce a hyperpolarizing shift in activation and slow deactivation. We also show that these mutations cause an increase in amplitude of the current produced by Na v 1.7 in response to slow, small depolarizations. These observations provide the first demonstration of altered sodium channel function associated with an inherited painful neuropathy and suggest that these physiological changes, which confer hyperexcitability on peripheral sensory and sympathetic neurons, contribute to symptom production in hereditary erythermalgia.

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Section: Discussionmentioning

confidence: 88%

Electrophysiological Properties of Mutant Na_v1.7 Sodium Channels in a Painful Inherited Neuropathy

Cummins¹,

Dib‐Hajj²,

Waxman³

2004

J. Neurosci.

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363

289

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“…It will also be intriguing to see whether any of these other genes show comparable alterations in expression or sequence especially in those species with extremely rapid EOD pulses. Na ϩ channel genes are highly constrained, as evidenced by the large number of amino acid replacements that change the properties of the Na ϩ current and lead to neurological, cardiac, and muscular diseases (15)(16)(17)(18)(19)(20). A critical step in the evolution of electric organs is the disabling of excitation-contraction so that the organ does not twitch when it discharges.…”

Section: Discussionmentioning

confidence: 99%

“…4B). Mutations flanking these sites in the S4-S5 linker DII in human Na ϩ channel genes disrupt slow inactivation (the propensity for Na ϩ channel to inactivate after prolonged usage) and are associated with muscle diseases (16,36).…”

Section: Convergent Amino Acid Replacements In Parts Of the Channel Imentioning

confidence: 99%

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Sodium channel genes and the evolution of diversity in communication signals of electric fishes: Convergent molecular evolution

Zakon

Zwickl

et al. 2006

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

143

126

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We investigated whether the evolution of electric organs and electric signal diversity in two independently evolved lineages of electric fishes was accompanied by convergent changes on the molecular level. We found that a sodium channel gene (Nav1.4a) that is expressed in muscle in nonelectric fishes has lost its expression in muscle and is expressed instead in the evolutionarily novel electric organ in both lineages of electric fishes. This gene appears to be evolving under positive selection in both lineages, facilitated by its restricted expression in the electric organ. This view is reinforced by the lack of evidence for selection on this gene in one electric species in which expression of this gene is retained in muscle. Amino acid replacements occur convergently in domains that influence channel inactivation, a key trait for shaping electric communication signals. Some amino acid replacements occur at or adjacent to sites at which disease-causing mutations have been mapped in human sodium channel genes, emphasizing that these replacements occur in functionally important domains. Selection appears to have acted on the final step in channel inactivation, but complementarily on the inactivation ''ball'' in one lineage, and its receptor site in the other lineage. Thus, changes in the expression and sequence of the same gene are associated with the independent evolution of signal complexity.animal communication ͉ electric organ ͉ channel inactivation ͉ protein evolution ͉ positive selection

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“…This sustained depolarization of the resting potential is due to sodium channels that do not inactivate completely, thereby conducting a persistent inward sodium current that depolarizes the fibre. (Bendahhou et al, 2002;Cannon, 2006).…”

Section: Molecular Pathophysiologymentioning

confidence: 99%

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

Matthews

Fialho

Tan

et al. 2009

Brain

198

226

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The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.

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Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5

Cited by 67 publications

References 31 publications

Electrophysiological Properties of Mutant Na_v1.7 Sodium Channels in a Painful Inherited Neuropathy

Electrophysiological Properties of Mutant Na_v1.7 Sodium Channels in a Painful Inherited Neuropathy

Sodium channel genes and the evolution of diversity in communication signals of electric fishes: Convergent molecular evolution

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

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Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5

Cited by 67 publications

References 31 publications

Electrophysiological Properties of Mutant Nav1.7 Sodium Channels in a Painful Inherited Neuropathy

Electrophysiological Properties of Mutant Nav1.7 Sodium Channels in a Painful Inherited Neuropathy

Sodium channel genes and the evolution of diversity in communication signals of electric fishes: Convergent molecular evolution

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

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Product

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Electrophysiological Properties of Mutant Na_v1.7 Sodium Channels in a Painful Inherited Neuropathy

Electrophysiological Properties of Mutant Na_v1.7 Sodium Channels in a Painful Inherited Neuropathy