Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0MYDHC)

• DOT Name: Sodium channel protein type 4 subunit alpha (SCN4A)
• Synonyms: SkM1; Sodium channel protein skeletal muscle subunit alpha; Sodium channel protein type IV subunit alpha; Voltage-gated sodium channel subunit alpha Nav1.4
• Gene Name: SCN4A
• Related Disease:
  Hyperkalemic periodic paralysis
  Hypokalemic periodic paralysis, type 1
  Paramyotonia congenita of Von Eulenburg
  SCN4A-related myopathy, autosomal recessive
  Congenital myasthenic syndrome 16
  Congenital myopathy
  Congenital myopathy 22A, classic
  Hypokalemic periodic paralysis, type 2
  Potassium-aggravated myotonia
  Acetazolamide-responsive myotonia
  Hypokalemic periodic paralysis
  Myotonia fluctuans
  Myotonia permanens
  Postsynaptic congenital myasthenic syndrome
• UniProt ID: SCN4A_HUMAN
• PDB ID: 6AGF; 6MBA; 6MC9
• Pfam ID: PF00520 ; PF06512
• Sequence:
  MARPSLCTLVPLGPECLRPFTRESLAAIEQRAVEEEARLQRNKQMEIEEPERKPRSDLEA
  GKNLPMIYGDPPPEVIGIPLEDLDPYYSNKKTFIVLNKGKAIFRFSATPALYLLSPFSVV
  RRGAIKVLIHALFSMFIMITILTNCVFMTMSDPPPWSKNVEYTFTGIYTFESLIKILARG
  FCVDDFTFLRDPWNWLDFSVIMMAYLTEFVDLGNISALRTFRVLRALKTITVIPGLKTIV
  GALIQSVKKLSDVMILTVFCLSVFALVGLQLFMGNLRQKCVRWPPPFNDTNTTWYSNDTW
  YGNDTWYGNEMWYGNDSWYANDTWNSHASWATNDTFDWDAYISDEGNFYFLEGSNDALLC
  GNSSDAGHCPEGYECIKTGRNPNYGYTSYDTFSWAFLALFRLMTQDYWENLFQLTLRAAG
  KTYMIFFVVIIFLGSFYLINLILAVVAMAYAEQNEATLAEDKEKEEEFQQMLEKFKKHQE
  ELEKAKAAQALEGGEADGDPAHGKDCNGSLDTSQGEKGAPRQSSSGDSGISDAMEELEEA
  HQKCPPWWYKCAHKVLIWNCCAPWLKFKNIIHLIVMDPFVDLGITICIVLNTLFMAMEHY
  PMTEHFDNVLTVGNLVFTGIFTAEMVLKLIAMDPYEYFQQGWNIFDSIIVTLSLVELGLA
  NVQGLSVLRSFRLLRVFKLAKSWPTLNMLIKIIGNSVGALGNLTLVLAIIVFIFAVVGMQ
  LFGKSYKECVCKIALDCNLPRWHMHDFFHSFLIVFRILCGEWIETMWDCMEVAGQAMCLT
  VFLMVMVIGNLVVLNLFLALLLSSFSADSLAASDEDGEMNNLQIAIGRIKLGIGFAKAFL
  LGLLHGKILSPKDIMLSLGEADGAGEAGEAGETAPEDEKKEPPEEDLKKDNHILNHMGLA
  DGPPSSLELDHLNFINNPYLTIQVPIASEESDLEMPTEEETDTFSEPEDSKKPPQPLYDG
  NSSVCSTADYKPPEEDPEEQAEENPEGEQPEECFTEACVQRWPCLYVDISQGRGKKWWTL
  RRACFKIVEHNWFETFIVFMILLSSGALAFEDIYIEQRRVIRTILEYADKVFTYIFIMEM
  LLKWVAYGFKVYFTNAWCWLDFLIVDVSIISLVANWLGYSELGPIKSLRTLRALRPLRAL
  SRFEGMRVVVNALLGAIPSIMNVLLVCLIFWLIFSIMGVNLFAGKFYYCINTTTSERFDI
  SEVNNKSECESLMHTGQVRWLNVKVNYDNVGLGYLSLLQVATFKGWMDIMYAAVDSREKE
  EQPQYEVNLYMYLYFVIFIIFGSFFTLNLFIGVIIDNFNQQKKKLGGKDIFMTEEQKKYY
  NAMKKLGSKKPQKPIPRPQNKIQGMVYDLVTKQAFDITIMILICLNMVTMMVETDNQSQL
  KVDILYNINMIFIIIFTGECVLKMLALRQYYFTVGWNIFDFVVVILSIVGLALSDLIQKY
  FVSPTLFRVIRLARIGRVLRLIRGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYSIFG
  MSNFAYVKKESGIDDMFNFETFGNSIICLFEITTSAGWDGLLNPILNSGPPDCDPNLENP
  GTSVKGDCGNPSIGICFFCSYIIISFLIVVNMYIAIILENFNVATEESSEPLGEDDFEMF
  YETWEKFDPDATQFIAYSRLSDFVDTLQEPLRIAKPNKIKLITLDLPMVPGDKIHCLDIL
  FALTKEVLGDSGEMDALKQTMEEKFMAANPSKVSYEPITTTLKRKHEEVCAIKIQRAYRR
  HLLQRSMKQASYMYRHSHDGSGDDAPEKEGLLANTMSKMYGHENGNSSSPSPEEKGEAGD
  AGPTMGLMPISPSDTAWPPAPPPGQTVRPGVKESLV
• Function: 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. Required for normal muscle fiber excitability, normal muscle contraction and relaxation cycles, and constant muscle strength in the presence of fluctuating K(+) levels.
• Reactome Pathway:
  Phase 0 - rapid depolarisation (R-HSA-5576892)
  Interaction between L1 and Ankyrins (R-HSA-445095)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperkalemic periodic paralysis	DIS21WOL	Definitive	Autosomal dominant	[1]
Hypokalemic periodic paralysis, type 1	DIS5GF2M	Definitive	Autosomal dominant	[2]
Paramyotonia congenita of Von Eulenburg	DISXYDU9	Definitive	Autosomal dominant	[3]
SCN4A-related myopathy, autosomal recessive	DIS9M11B	Definitive	Autosomal recessive	[4]
Congenital myasthenic syndrome 16	DISUTJ3P	Strong	Autosomal recessive	[3]
Congenital myopathy	DISLSK9G	Strong	Autosomal recessive	[3]
Congenital myopathy 22A, classic	DISVHGJ2	Strong	Autosomal recessive	[5]
Hypokalemic periodic paralysis, type 2	DISSQ9Z3	Strong	Autosomal dominant	[3]
Potassium-aggravated myotonia	DISRO6ZH	Strong	Autosomal dominant	[6]
Acetazolamide-responsive myotonia	DIS1CVOM	Supportive	Autosomal dominant	[7]
Hypokalemic periodic paralysis	DISVIXI1	Supportive	Autosomal dominant	[8]
Myotonia fluctuans	DISGCBNH	Supportive	Autosomal dominant	[9]
Myotonia permanens	DISPG36V	Supportive	Autosomal dominant	[10]
Postsynaptic congenital myasthenic syndrome	DIS92VN2	Supportive	Autosomal recessive	[11]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Sodium channel protein type 4 subunit alpha (SCN4A).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sodium channel protein type 4 subunit alpha (SCN4A).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Sodium channel protein type 4 subunit alpha (SCN4A).	[17]

4 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the activity of Sodium channel protein type 4 subunit alpha (SCN4A).	[13]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Sodium channel protein type 4 subunit alpha (SCN4A).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sodium channel protein type 4 subunit alpha (SCN4A).	[16]
Chloroxylenol	DMM75WZ	Investigative	Chloroxylenol affects the activity of Sodium channel protein type 4 subunit alpha (SCN4A).	[18]

References

• [1] Identification of a mutation in the gene causing hyperkalemic periodic paralysis. Cell. 1991 Nov 29;67(5):1021-7. doi: 10.1016/0092-8674(91)90374-8.
• [2] Temperature-sensitive sodium channelopathy with heat-induced myotonia and cold-induced paralysis. Neurology. 2000 Jun 13;54(11):2179-81. doi: 10.1212/wnl.54.11.2179.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [5] Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy. Brain. 2016 Mar;139(Pt 3):674-91. doi: 10.1093/brain/awv352. Epub 2015 Dec 22.
• [6] A Novel De Novo Heterozygous SCN4a Mutation Causing Congenital Myopathy, Myotonia and Multiple Congenital Anomalies. J Neuromuscul Dis. 2019;6(4):467-473. doi: 10.3233/JND-190425.
• [7] Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis. Neurology. 1994 Aug;44(8):1500-3. doi: 10.1212/wnl.44.8.1500.
• [8] Hypokalemic Periodic Paralysis. 2002 Apr 30 [updated 2018 Jul 26]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [9] Myotonia fluctuans. A third type of muscle sodium channel disease. Arch Neurol. 1994 Nov;51(11):1095-102. doi: 10.1001/archneur.1994.00540230033009.
• [10] Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III-IV linker. J Physiol. 1993 Oct;470:13-22. doi: 10.1113/jphysiol.1993.sp019843.
• [11] Congenital Myasthenic Syndromes Overview. 2003 May 9 [updated 2021 Dec 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [12] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [13] Inhibitory effects of cannabidiol on voltage-dependent sodium currents. J Biol Chem. 2018 Oct 26;293(43):16546-16558. doi: 10.1074/jbc.RA118.004929. Epub 2018 Sep 14.
• [14] Adipogenic Effects and Gene Expression Profiling of Firemaster? 550 Components in Human Primary Preadipocytes. Environ Health Perspect. 2017 Sep 14;125(9):097013. doi: 10.1289/EHP1318.
• [15] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [16] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Phenol derivatives accelerate inactivation kinetics in one inactivation-deficient mutant human skeletal muscle Na(+) channel. Eur J Pharmacol. 2001 Mar 23;416(1-2):11-8. doi: 10.1016/s0014-2999(01)00857-3.