Last update 19 Sep 2024

SCN4A

Last update 19 Sep 2024

Basic Info

Synonyms

电压门控钠离子通道NAV1.4, HYKPP, HYPP

+ [10]

Introduction

Pore-forming subunit of a voltage-gated sodium channel complex through which Na(+) ions pass in accordance with their electrochemical gradient. Alternates between resting, activated and inactivated states (PubMed:12766226, PubMed:29992740, PubMed:30190309, PubMed:15318338, PubMed:16890191, PubMed:18690054, PubMed:17898326, PubMed:19347921, PubMed:25707578, PubMed:26700687). Required for normal muscle fiber excitability, normal muscle contraction and relaxation cycles, and constant muscle strength in the presence of fluctuating K(+) levels (PubMed:12766226, PubMed:15318338, PubMed:16890191, PubMed:19347921, PubMed:25707578, PubMed:26700687, PubMed:26659129).

Drugs associated with SCN4A

Neosaxitoxin

Target

SCN4A

Mechanism

SCN4A blockers

Active Org.-

Originator Org.

Grunenthal SA

Active Indication-

Inactive Indication

Anesthesia

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

ST-410

Target

SCN4A

Mechanism

SCN4A blockers

Active Org.-

Originator Org.

SiteOne Therapeutics, Inc.

Active Indication-

Inactive Indication

Pain

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with SCN4A

NCT03399435 / TerminatedPhase 1

An Exploratory Phase I Randomized, Single-site, Double-blind, Active-controlled, Parallel-group, Single-administration, Dose-escalation Trial to Investigate the Safety and Tolerability of Neosaxitoxin Alone and in Combination With Bupivacaine (With and Without Epinephrine), in Perineural Administrations for Brachial Plexus Blockade in Healthy Subjects

Neosaxitoxin is a new compound that is in clinical development as local anesthetic for surgical anesthesia and postoperative analgesia.
The primary objective of this study is to evaluate the systemic and local safety and tolerability of ascending doses of neosaxitoxin alone and in combination with fixed doses of bupivacaine (with and without epinephrine), following brachial plexus blockade in healthy male subjects.
Secondary objectives:
Evaluate the pharmacodynamics (PD) of ascending doses of neosaxitoxin, alone and in combination with fixed doses of bupivacaine (with and without epinephrine), following brachial plexus blockade.
Characterize the pharmacokinetics (PK) of neosaxitoxin and bupivacaine after brachial plexus blockade with neosaxitoxin alone or different drug combinations: neosaxitoxin and epinephrine, neosaxitoxin and bupivacaine, or neosaxitoxin and bupivacaine and epinephrine.

Start Date30 Jan 2018

Sponsor / Collaborator

Grünenthal GmbH

NCT01786655 / CompletedPhase 1IIT

Neosaxitoxin (NeoSTX) Alone and in Combination With Bupivacaine as Prolonged Duration Local Anesthetics: A Phase I Investigator-initiated Dose Escalation Study

The primary aim of this Phase 1 study is to evaluate the systemic safety of a novel prolonged-duration local anesthetic, Neosaxitoxin (NeoSTX), given by subcutaneous injection in combination with the commonly used local anesthetic, bupivacaine, and epinephrine.
The investigators hypothesize that a "minimal adverse effect threshold" NeoSTX dose for subcutaneous administration in combination with bupivacaine 0.2% and epinephrine 5mcg/ml respectively, can be defined for awake, young adult healthy volunteer subjects. At the same time, the pharmacokinetics of NeoSTX when delivered subcutaneously will be determined.

Start Date01 May 2013

Sponsor / Collaborator

The Children's Hospital Corp.

NCT00273065 / CompletedPhase 1IIT

Phase 1 Study of Local Infiltration of Neosaxitoxin as a Local Anesthetic

The purpose of this study is to evaluate the local anesthetic properties of neosaxitoxin in humans

Start Date01 May 2005

Sponsor / Collaborator

University of Chile

100 Clinical Results associated with SCN4A

100 Translational Medicine associated with SCN4A

0 Patents (Medical) associated with SCN4A

714

Literatures (Medical) associated with SCN4A

01 Dec 2024·Molecular Biology Reports

Clinical and molecular characterization of myotonia congenita using whole-exome sequencing in Egyptian patients

Article

Author: Dawoud, Heba ; Ashaat, Engy A ; Azmy, Ashraf ; Galal, Eman Reda ; Awady, Heba El ; Elhusseny, Yasmine ; Ashaat, Neveen A ; Elaraby, Nesma M ; Ahmed, Hoda A ; Metwally, Ammal M

BACKGROUNDMyotonia Congenita (MC) is a rare disease classified into two major forms; Thomsen and Becker disease caused by mutations in the CLCN1 gene, which affects muscle excitability and encodes voltage-gated chloride channels (CLC-1). While, there are no data regarding the clinical and molecular characterization of myotonia in Egyptian patients.METHODSHerein, we report seven Egyptian MC patients from six unrelated families. Following the clinical diagnosis, whole-exome sequencing (WES) was performed for genetic diagnosis. Various in silico prediction tools were utilized to interpret variant pathogenicity. The candidate variants were then validated using Sanger sequencing technique.RESULTSIn total, seven cases were recruited. The ages at the examination were ranged from eight months to nineteen years. Clinical manifestations included warm-up phenomenon, hand grip, and percussion myotonia. Electromyography was performed in all patients and revealed myotonic discharges. Molecular genetic analysis revealed five different variants. Of them, we identified two novel variants in the CLCN1 gene ( c.1583G > C; p.Gly528Ala and c.2203_2216del;p.Thr735ValfsTer57) and three known variants in the CLCN1 and SCN4A gene. According to in silico tools, the identified novel variants were predicted to have deleterious effects.CONCLUSIONSAs the first study to apply WES among Egyptian MC patients, our findings reported two novel heterozygous variants that expand the CLCN1 mutational spectrum for MC diagnosis. These results further confirm that genetic testing is essential for early diagnosis of MC, which affects follow-up treatment and prognostic assessment in clinical practice.

31 Aug 2024·The FASEB Journal

Diverse biophysical mechanisms in voltage‐gated sodium channel Na_v1.4 variants associated with myotonia

Article

Author: Tikhonova, Tatiana B. ; Vassilevski, Alexander A. ; Sharkov, Artem A. ; Zhorov, Boris S.

AbstractMutations in SCN4A gene encoding Nav1.4 channel α‐subunit, are known to cause neuromuscular disorders such as myotonia or paralysis. Here, we study the effect of two amino acid replacements, K1302Q and G1306E, in the DIII–IV loop of the channel, corresponding to mutations found in patients with myotonia. We combine clinical, electrophysiological, and molecular modeling data to provide a holistic picture of the molecular mechanisms operating in mutant channels and eventually leading to pathology. We analyze the existing clinical data for patients with the K1302Q substitution, which was reported for adults with or without myotonia phenotypes, and report two new unrelated patients with the G1306E substitution, who presented with severe neonatal episodic laryngospasm and childhood‐onset myotonia. We provide a functional analysis of the mutant channels by expressing Nav1.4 α‐subunit in Xenopus oocytes in combination with β1 subunit and recording sodium currents using two‐electrode voltage clamp. The K1302Q variant exhibits abnormal voltage dependence of steady‐state fast inactivation, being the likely cause of pathology. K1302Q does not lead to decelerated fast inactivation, unlike several other myotonic mutations such as G1306E. For both mutants, we observe increased window currents corresponding to a larger population of channels available for activation. To elaborate the structural rationale for our experimental data, we explore the contacts involving K/Q1302 and E1306 in the AlphaFold2 model of wild‐type Nav1.4 and Monte Carlo‐minimized models of mutant channels. Our data provide the missing evidence to support the classification of K1302Q variant as likely pathogenic and may be used by clinicians.

01 Jun 2024·Epilepsia Open

Idiopathic generalized epilepsy in a family with SCN4A‐related myotonia

Article

Author: Labalme, Audrey ; Sanlaville, Damien ; Chatron, Nicolas ; Gambardella, Antonio ; Fortunato, Francesco ; Januel, Louis ; Annesi, Grazia ; Gagliardi, Monica ; Procopio, Radha ; Talarico, Mariagrazia ; Sammarra, Ilaria ; Lesca, Gaetan ; Valentino, Paola

AbstractObjectivesMyotonia is a clinical sign typical of a group of skeletal muscle channelopathies, the non‐dystrophic myotonias. These disorders are electrophysiologically characterized by altered membrane excitability, due to specific genetic variants in known causative genes (CLCN1 and SCN4A). Juvenile Myoclonic Epilepsy (JME) is an epileptic syndrome identified as idiopathic generalized epilepsy, its genetics is complex and still unclarified. The co‐occurrence of these two phenotypes is rare and the causes likely have a genetic background. In this study, we have genetically investigated an Italian family in which co‐segregates myotonia, JME, or abnormal EEG without seizures was observed.MethodsAll six individuals of the family, 4 affected and 2 unaffected, were clinically evaluated; EMG and EEG examinations were performed. For genetic testing, Exome Sequencing was performed for the six family members and Sanger sequencing was used to confirm the candidate variant.ResultsFour family members, the mother and three siblings, were affected by myotonia. Moreover, EEG recordings revealed interictal generalized sharp‐wave discharges in all affected individuals, and two siblings were affected by JME. All four affected members share the same identified variant, c.644 T > C, p.Ile215Thr, in SCN4A gene. Variants that could account for the epileptic phenotype alone, separately from the myotonic one, were not identified.SignificanceThese results provide supporting evidence that both myotonic and epileptic phenotypes could share a common genetic background, due to variants in SCN4A gene. SCN4A pathogenic variants, already known to be causative of myotonia, likely increase the susceptibility to epilepsy in our family.Plain Language SummaryThis study analyzed all members of an Italian family, in which the mother and three siblings had myotonia and epilepsy. Genetic analysis allowed to identify a variant in the SCN4A gene, which appears to be the cause of both clinical signs in this family.

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