Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUXJRM1)

• DOT Name: Metal transporter CNNM4 (CNNM4)
• Synonyms: Ancient conserved domain-containing protein 4; Cyclin-M4
• Gene Name: CNNM4
• Related Disease:
  Achromatopsia
  Adenocarcinoma
  Colon cancer
  Colon carcinoma
  Jalili syndrome
  Advanced cancer
  Amelogenesis imperfecta
  Cone-rod dystrophy 2
  Disorder of orbital region
  Pathologic nystagmus
  Trichohepatoenteric syndrome
  Cone-rod dystrophy
  Familial primary hypomagnesemia
  Malabsorption syndrome
  Neurofibromatosis type 1
  Neoplasm
• UniProt ID: CNNM4_HUMAN
• PDB ID: 6G52; 6RS2
• Pfam ID: PF00571 ; PF01595
• Sequence:
  MAPVGGGGRPVGGPARGRLLLAAPVLLVLLWALGARGQGSPQQGTIVGMRLASCNKSCGT
  NPDGIIFVSEGSTVNLRLYGYSLGNISSNLISFTEVDDAETLHKSTSCLELTKDLVVQQL
  VNVSRGNTSGVLVVLTKFLRRSESMKLYALCTRAQPDGPWLKWTDKDSLLFMVEEPGRFL
  PLWLHILLITVLLVLSGIFSGLNLGLMALDPMELRIVQNCGTEKERRYARKIEPIRRKGN
  YLLCSLLLGNVLVNTSLTILLDNLIGSGLMAVASSTIGIVIFGEILPQALCSRHGLAVGA
  NTILLTKFFMLLTFPLSFPISKLLDFFLGQEIRTVYNREKLMEMLKVTEPYNDLVKEELN
  MIQGALELRTKTVEDIMTQLQDCFMIRSDAILDFNTMSEIMESGYTRIPVFEDEQSNIVD
  ILYVKDLAFVDPDDCTPLKTITRFYNHPVHFVFHDTKLDAMLEEFKKGKSHLAIVQKVNN
  EGEGDPFYEVLGLVTLEDVIEEIIKSEILDESDMYTDNRSRKRVSEKNKRDFSAFKDADN
  ELKVKISPQLLLAAHRFLATEVSQFSPSLISEKILLRLLKYPDVIQELKFDEHNKYYARH
  YLYTRNKPADYFILILQGKVEVEAGKENMKFETGAFSYYGTMALTSVPSDRSPAHPTPLS
  RSASLSYPDRTDVSTAATLAGSSNQFGSSVLGQYISDFSVRALVDLQYIKITRQQYQNGL
  LASRMENSPQFPIDGCTTHMENLAEKSELPVVDETTTLLNERNSLLHKASHENAI
• Function: Probable metal transporter. The interaction with the metal ion chaperone COX11 suggests that it may play a role in sensory neuron functions. May play a role in biomineralization and retinal function.
• Tissue Specificity: Widely expressed. Highly expressed in heart.

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Achromatopsia	DISKL51I	Definitive	Genetic Variation	[1]
Adenocarcinoma	DIS3IHTY	Definitive	Genetic Variation	[2]
Colon cancer	DISVC52G	Definitive	Altered Expression	[2]
Colon carcinoma	DISJYKUO	Definitive	Altered Expression	[2]
Jalili syndrome	DIS3FJ55	Definitive	Autosomal recessive	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Amelogenesis imperfecta	DISGYR9E	Strong	Genetic Variation	[5]
Cone-rod dystrophy 2	DISX2RWY	Strong	Genetic Variation	[5]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[6]
Pathologic nystagmus	DIS1QSPO	Strong	Genetic Variation	[6]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[6]
Cone-rod dystrophy	DISY9RWN	moderate	Genetic Variation	[7]
Familial primary hypomagnesemia	DIS6TTKI	moderate	Biomarker	[8]
Malabsorption syndrome	DISGMUVS	moderate	Biomarker	[8]
Neurofibromatosis type 1	DIS53JH9	moderate	Genetic Variation	[9]
Neoplasm	DISZKGEW	Limited	Biomarker	[10]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Metal transporter CNNM4 (CNNM4) decreases the response to substance of Arsenic trioxide.	[24]

2 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 Metal transporter CNNM4 (CNNM4).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Metal transporter CNNM4 (CNNM4).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Metal transporter CNNM4 (CNNM4).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Metal transporter CNNM4 (CNNM4).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Metal transporter CNNM4 (CNNM4).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Metal transporter CNNM4 (CNNM4).	[15]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Metal transporter CNNM4 (CNNM4).	[16]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Metal transporter CNNM4 (CNNM4).	[17]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Metal transporter CNNM4 (CNNM4).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Metal transporter CNNM4 (CNNM4).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Metal transporter CNNM4 (CNNM4).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Metal transporter CNNM4 (CNNM4).	[22]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Metal transporter CNNM4 (CNNM4).	[23]

References

• [1] Cone-rod dystrophy and amelogenesis imperfecta (Jalili syndrome): phenotypes and environs.Eye (Lond). 2010 Nov;24(11):1659-68. doi: 10.1038/eye.2010.103. Epub 2010 Aug 13.
• [2] Membrane protein CNNM4-dependent Mg2+ efflux suppresses tumor progression.J Clin Invest. 2014 Dec;124(12):5398-410. doi: 10.1172/JCI76614. Epub 2014 Oct 27.
• [3] 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.
• [4] Cnnm4 deficiency suppresses Ca(2+) signaling and promotes cell proliferation in the colon epithelia.Oncogene. 2019 May;38(20):3962-3969. doi: 10.1038/s41388-019-0682-0. Epub 2019 Jan 22.
• [5] Jalili Syndrome: Cross-sectional and Longitudinal Features of Seven Patients With Cone-Rod Dystrophy and Amelogenesis Imperfecta.Am J Ophthalmol. 2018 Apr;188:123-130. doi: 10.1016/j.ajo.2018.01.029. Epub 2018 Feb 5.
• [6] A novel mutation and variable phenotypic expression in a large consanguineous pedigree with Jalili syndrome.Eye (Lond). 2016 Nov;30(11):1424-1432. doi: 10.1038/eye.2016.137. Epub 2016 Jul 15.
• [7] Mutations in CNNM4 cause recessive cone-rod dystrophy with amelogenesis imperfecta.Am J Hum Genet. 2009 Feb;84(2):259-65. doi: 10.1016/j.ajhg.2009.01.006. Epub 2009 Feb 5.
• [8] Basolateral Mg2+ extrusion via CNNM4 mediates transcellular Mg2+ transport across epithelia: a mouse model.PLoS Genet. 2013;9(12):e1003983. doi: 10.1371/journal.pgen.1003983. Epub 2013 Dec 5.
• [9] Cone-rod dystrophy associated with amelogenesis imperfecta in a child with neurofibromatosis type 1.Ophthalmic Genet. 2012 Mar;33(1):34-8. doi: 10.3109/13816810.2011.592178. Epub 2011 Jul 5.
• [10] CFP suppresses breast cancer cell growth by TES-mediated upregulation of the transcription factor DDIT3.Oncogene. 2019 Jun;38(23):4560-4573. doi: 10.1038/s41388-019-0739-0. Epub 2019 Feb 12.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [14] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ Toxicol. 2018 Nov;33(11):1168-1181. doi: 10.1002/tox.22623. Epub 2018 Aug 27.
• [17] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [18] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [24] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.