Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWY7DS0)

• DOT Name: Sodium leak channel NALCN (NALCN)
• Synonyms: CanIon; Sodium leak channel non-selective protein; Voltage gated channel-like protein 1
• Gene Name: NALCN
• Related Disease:
  Congenital contractures of the limbs and face, hypotonia, and developmental delay
  Hypotonia, infantile, with psychomotor retardation and characteristic facies 1
  Nervous system disease
  Arthrogryposis
  Arthrogryposis, distal, type 1A
  Brain disease
  Distal arthrogryposis
  Gout
  Neurodegeneration with brain iron accumulation 2A
  Sleep disorder
  Mental disorder
  Psychotic disorder
  Digitotalar dysmorphism
  Freeman-Sheldon syndrome
  Hypotonia, infantile, with psychomotor retardation and characteristic facies
  Sheldon-hall syndrome
  HIV-associated dementia
  Hypotonia, infantile, with psychomotor retardation and characteristic facies 2
  Intellectual disability
• UniProt ID: NALCN_HUMAN
• PDB ID: 6XIW; 7CM3; 7SX3; 7SX4; 7WJI
• Pfam ID: PF00520
• Sequence:
  MLKRKQSSRVEAQPVTDFGPDESLSDNADILWINKPWVHSLLRICAIISVISVCMNTPMT
  FEHYPPLQYVTFTLDTLLMFLYTAEMIAKMHIRGIVKGDSSYVKDRWCVFDGFMVFCLWV
  SLVLQVFEIADIVDQMSPWGMLRIPRPLIMIRAFRIYFRFELPRTRITNILKRSGEQIWS
  VSIFLLFFLLLYGILGVQMFGTFTYHCVVNDTKPGNVTWNSLAIPDTHCSPELEEGYQCP
  PGFKCMDLEDLGLSRQELGYSGFNEIGTSIFTVYEAASQEGWVFLMYRAIDSFPRWRSYF
  YFITLIFFLAWLVKNVFIAVIIETFAEIRVQFQQMWGSRSSTTSTATTQMFHEDAAGGWQ
  LVAVDVNKPQGRAPACLQKMMRSSVFHMFILSMVTVDVIVAASNYYKGENFRRQYDEFYL
  AEVAFTVLFDLEALLKIWCLGFTGYISSSLHKFELLLVIGTTLHVYPDLYHSQFTYFQVL
  RVVRLIKISPALEDFVYKIFGPGKKLGSLVVFTASLLIVMSAISLQMFCFVEELDRFTTF
  PRAFMSMFQILTQEGWVDVMDQTLNAVGHMWAPVVAIYFILYHLFATLILLSLFVAVILD
  NLELDEDLKKLKQLKQSEANADTKEKLPLRLRIFEKFPNRPQMVKISKLPSDFTVPKIRE
  SFMKQFIDRQQQDTCCLLRSLPTTSSSSCDHSKRSAIEDNKYIDQKLRKSVFSIRARNLL
  EKETAVTKILRACTRQRMLSGSFEGQPAKERSILSVQHHIRQERRSLRHGSNSQRISRGK
  SLETLTQDHSNTVRYRNAQREDSEIKMIQEKKEQAEMKRKVQEEELRENHPYFDKPLFIV
  GREHRFRNFCRVVVRARFNASKTDPVTGAVKNTKYHQLYDLLGLVTYLDWVMIIVTICSC
  ISMMFESPFRRVMHAPTLQIAEYVFVIFMSIELNLKIMADGLFFTPTAVIRDFGGVMDIF
  IYLVSLIFLCWMPQNVPAESGAQLLMVLRCLRPLRIFKLVPQMRKVVRELFSGFKEIFLV
  SILLLTLMLVFASFGVQLFAGKLAKCNDPNIIRREDCNGIFRINVSVSKNLNLKLRPGEK
  KPGFWVPRVWANPRNFNFDNVGNAMLALFEVLSLKGWVEVRDVIIHRVGPIHGIYIHVFV
  FLGCMIGLTLFVGVVIANFNENKGTALLTVDQRRWEDLKSRLKIAQPLHLPPRPDNDGFR
  AKMYDITQHPFFKRTIALLVLAQSVLLSVKWDVEDPVTVPLATMSVVFTFIFVLEVTMKI
  IAMSPAGFWQSRRNRYDLLVTSLGVVWVVLHFALLNAYTYMMGACVIVFRFFSICGKHVT
  LKMLLLTVVVSMYKSFFIIVGMFLLLLCYAFAGVVLFGTVKYGENINRHANFSSAGKAIT
  VLFRIVTGEDWNKIMHDCMVQPPFCTPDEFTYWATDCGNYAGALMYFCSFYVIIAYIMLN
  LLVAIIVENFSLFYSTEEDQLLSYNDLRHFQIIWNMVDDKREGVIPTFRVKFLLRLLRGR
  LEVDLDKDKLLFKHMCYEMERLHNGGDVTFHDVLSMLSYRSVDIRKSLQLEELLAREQLE
  YTIEEEVAKQTIRMWLKKCLKRIRAKQQQSCSIIHSLRESQQQELSRFLNPPSIETTQPS
  EDTNANSQDNSMQPETSSQQQLLSPTLSDRGGSRQDAADAGKPQRKFGQWRLPSAPKPIS
  HSVSSVNLRFGGRTTMKSVVCKMNPMTDAASCGSEVKKWWTRQLTVESDESGDDLLDI
• Function: Voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability. NALCN channel functions as a multi-protein complex, which consists at least of NALCN, NALF1, UNC79 and UNC80. NALCN is the voltage-sensing, pore-forming subunit of the NALCN channel complex. NALCN channel complex is constitutively active and conducts monovalent cations but is blocked by physiological concentrations of extracellular divalent cations. In addition to its role in regulating neuronal excitability, is required for normal respiratory rhythm, systemic osmoregulation by controlling the serum sodium concentration and in the regulation of the intestinal pace-making activity in the interstitial cells of Cajal. NALCN channel is also activated by neuropeptides such as neurotensin and substance P (SP) through a SRC family kinases-dependent pathway. In addition, NALCN activity is enhanced/modulated by several GPCRs, such as CHRM3.
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital contractures of the limbs and face, hypotonia, and developmental delay	DIS1JHCE	Definitive	Autosomal dominant	[1]
Hypotonia, infantile, with psychomotor retardation and characteristic facies 1	DIS8ZUPE	Definitive	Autosomal recessive	[2]
Nervous system disease	DISJ7GGT	Definitive	Genetic Variation	[3]
Arthrogryposis	DISC81CM	Strong	Genetic Variation	[4]
Arthrogryposis, distal, type 1A	DISD8IKM	Strong	GermlineCausalMutation	[1]
Brain disease	DIS6ZC3X	Strong	Biomarker	[5]
Distal arthrogryposis	DIS3QIEL	Strong	Biomarker	[1]
Gout	DISHC0U7	Strong	Genetic Variation	[6]
Neurodegeneration with brain iron accumulation 2A	DIS9XEBF	Strong	Genetic Variation	[2]
Sleep disorder	DIS3JP1U	Strong	Genetic Variation	[7]
Mental disorder	DIS3J5R8	moderate	Genetic Variation	[8]
Psychotic disorder	DIS4UQOT	moderate	Genetic Variation	[8]
Digitotalar dysmorphism	DISOW5Q1	Supportive	Autosomal dominant	[1]
Freeman-Sheldon syndrome	DIS7V9PS	Supportive	Autosomal dominant	[1]
Hypotonia, infantile, with psychomotor retardation and characteristic facies	DISFA88I	Supportive	Autosomal recessive	[2]
Sheldon-hall syndrome	DISOCVMC	Supportive	Autosomal dominant	[1]
HIV-associated dementia	DIS8OCOC	Limited	Genetic Variation	[9]
Hypotonia, infantile, with psychomotor retardation and characteristic facies 2	DISJAND1	Limited	Biomarker	[10]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Sodium leak channel NALCN (NALCN).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Sodium leak channel NALCN (NALCN).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Sodium leak channel NALCN (NALCN).	[17]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR increases the methylation of Sodium leak channel NALCN (NALCN).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sodium leak channel NALCN (NALCN).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Sodium leak channel NALCN (NALCN).	[13]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Sodium leak channel NALCN (NALCN).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sodium leak channel NALCN (NALCN).	[16]

References

• [1] De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. Am J Hum Genet. 2015 Mar 5;96(3):462-73. doi: 10.1016/j.ajhg.2015.01.003. Epub 2015 Feb 12.
• [2] Recessive truncating NALCN mutation in infantile neuroaxonal dystrophy with facial dysmorphism. J Med Genet. 2013 Aug;50(8):515-20. doi: 10.1136/jmedgenet-2013-101634. Epub 2013 Jun 7.
• [3] Novel NALCN biallelic truncating mutations in siblings with IHPRF1 syndrome.Clin Genet. 2018 Jun;93(6):1245-1247. doi: 10.1111/cge.13162. Epub 2018 Feb 5.
• [4] NALCN channelopathies: Distinguishing gain-of-function and loss-of-function mutations.Neurology. 2016 Sep 13;87(11):1131-9. doi: 10.1212/WNL.0000000000003095. Epub 2016 Aug 24.
• [5] Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy. Am J Hum Genet. 2016 Jan 7;98(1):210-5. doi: 10.1016/j.ajhg.2015.11.013. Epub 2015 Dec 17.
• [6] Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. Clin Pharmacol Ther. 2015 May;97(5):518-25.
• [7] Biallelic mutations in NALCN: Expanding the genotypic and phenotypic spectra of IHPRF1.Am J Med Genet A. 2018 Feb;176(2):431-437. doi: 10.1002/ajmg.a.38543. Epub 2017 Nov 23.
• [8] A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder.Schizophr Res. 2010 Dec;124(1-3):192-9. doi: 10.1016/j.schres.2010.09.002.
• [9] Genome-wide association study of neurocognitive impairment and dementia in HIV-infected adults.Am J Med Genet B Neuropsychiatr Genet. 2012 Sep;159B(6):669-83. doi: 10.1002/ajmg.b.32071. Epub 2012 May 24.
• [10] Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).Hum Genet. 2018 Sep;137(9):753-768. doi: 10.1007/s00439-018-1929-5. Epub 2018 Aug 23.
• [11] 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.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [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] Gene expression network regulated by DNA methylation and microRNA during microcystin-leucine arginine induced malignant transformation in human hepatocyte L02 cells. Toxicol Lett. 2018 Jun 1;289:42-53. doi: 10.1016/j.toxlet.2018.03.003. Epub 2018 Mar 5.