Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSME34W)

• DOT Name: Calcium load-activated calcium channel (TMCO1)
• Synonyms: CLAC channel; GEL complex subunit TMCO1; Transmembrane and coiled-coil domain-containing protein 1; Transmembrane and coiled-coil domains protein 4; Xenogeneic cross-immune protein PCIA3
• Gene Name: TMCO1
• Related Disease:
  Bone development disease
  Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1
  Obsolete cerebrofaciothoracic dysplasia
  Advanced cancer
  Angle-closure glaucoma
  Congenital fiber-type disproportion myopathy
  Epilepsy
  Megalencephalic leukoencephalopathy with subcortical cysts
  Open-angle glaucoma
  Osteoporosis
  Primary angle-closure glaucoma
  Glaucoma/ocular hypertension
  Intellectual disability
• UniProt ID: TMCO1_HUMAN
• PDB ID: 6W6L
• Pfam ID: PF01956
• Sequence:
  MPRKRKCDLRAVRVGLLLGGGGVYGSRFRFTFPGCRALSPWRVRVQRRRCEMSTMFADTL
  LIVFISVCTALLAEGITWVLVYRTDKYKRLKAEVEKQSKKLEKKKETITESAGRQQKKKI
  ERQEEKLKNNNRDLSMVRMKSMFAIGFCFTALMGMFNSIFDGRVVAKLPFTPLSYIQGLS
  HRNLLGDDTTDCSFIFLYILCTMSIRQNIQKILGLAPSRAATKQAGGFLGPPPPSGKFS
• Function: Calcium-selective channel required to prevent calcium stores from overfilling, thereby playing a key role in calcium homeostasis. In response to endoplasmic reticulum (ER) overloading, assembles into a homotetramer, forming a functional calcium-selective channel, regulating the calcium content in endoplasmic reticulum store. Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes. The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions. Within the MPT complex, the GEL subcomplex may mediate insertion of transmembrane regions into the membrane.
• Tissue Specificity: Widely expressed in adult and fetal tissues, with higher levels in thymus, prostate, testis and small intestine and lower levels in brain, placenta, lung and kidney . Present in most tissues in the eye, including the trabecular meshwork and retina (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone development disease	DISVKAZS	Definitive	Biomarker	[1]
Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1	DISJX1JQ	Definitive	Autosomal recessive	[1]
Obsolete cerebrofaciothoracic dysplasia	DIS1E4N3	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Angle-closure glaucoma	DISZ95KY	Strong	Genetic Variation	[4]
Congenital fiber-type disproportion myopathy	DISU9T2M	Strong	Genetic Variation	[5]
Epilepsy	DISBB28L	Strong	Genetic Variation	[5]
Megalencephalic leukoencephalopathy with subcortical cysts	DISK9A1M	Strong	Genetic Variation	[6]
Open-angle glaucoma	DISSZEE8	Strong	Genetic Variation	[7]
Osteoporosis	DISF2JE0	Strong	Biomarker	[3]
Primary angle-closure glaucoma	DISX8UKZ	Strong	Genetic Variation	[4]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Genetic Variation	[8]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Calcium load-activated calcium channel (TMCO1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calcium load-activated calcium channel (TMCO1).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Calcium load-activated calcium channel (TMCO1).	[11]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Calcium load-activated calcium channel (TMCO1).	[12]

References

• [1] Homozygous frameshift mutation in TMCO1 causes a syndrome with craniofacial dysmorphism, skeletal anomalies, and mental retardation. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):258-63. doi: 10.1073/pnas.0908457107. Epub 2009 Dec 14.
• [2] Cerebrofaciothoracic dysplasia: Four new patients with a recurrent TMCO1 pathogenic variant. Am J Med Genet A. 2019 Jan;179(1):43-49. doi: 10.1002/ajmg.a.60678. Epub 2018 Dec 17.
• [3] TMCO1-mediated Ca(2+) leak underlies osteoblast functions via CaMKII signaling.Nat Commun. 2019 Apr 8;10(1):1589. doi: 10.1038/s41467-019-09653-5.
• [4] Association of known common genetic variants with primary open angle, primary angle closure, and pseudoexfoliation glaucoma in Pakistani cohorts.Mol Vis. 2014 Nov 4;20:1471-9. eCollection 2014.
• [5] A novel biallelic loss-of-function mutation in TMCO1 gene confirming and expanding the phenotype spectrum of cerebro-facio-thoracic dysplasia.Am J Med Genet A. 2019 Jul;179(7):1338-1345. doi: 10.1002/ajmg.a.61168. Epub 2019 May 18.
• [6] Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts.Hum Genet. 2002 Mar;110(3):279-83. doi: 10.1007/s00439-002-0682-x. Epub 2002 Feb 8.
• [7] A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci.Nat Commun. 2018 Jun 11;9(1):2278. doi: 10.1038/s41467-018-04555-4.
• [8] Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma.Nat Genet. 2018 Aug;50(8):1067-1071. doi: 10.1038/s41588-018-0176-y. Epub 2018 Jul 27.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.