Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAZFPF5)

• DOT Name: DNA-binding protein SMUBP-2 (IGHMBP2)
• Synonyms: EC 3.6.4.12; EC 3.6.4.13; ATP-dependent helicase IGHMBP2; Glial factor 1; GF-1; Immunoglobulin mu-binding protein 2
• Gene Name: IGHMBP2
• Related Disease:
  Autosomal recessive distal spinal muscular atrophy 1
  Charcot-Marie-Tooth disease axonal type 2S
  Hereditary peripheral neuropathy
  Autonomic nervous system disorder
  Breast cancer
  Breast carcinoma
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease type 2
  Congenital myopathy
  Dysautonomia
  Motor neurone disease
  Motor peripheral neuropathy
  Myopathy
  Peripheral neuropathy
  Polyneuropathy
  Progressive multifocal leukoencephalopathy
  Respiratory failure
  Spinal muscular atrophy
  Spinal muscular atrophy, type 1
  Peripheral sensory neuropathies
• UniProt ID: SMBP2_HUMAN
• PDB ID: 1MSZ; 2LRR; 4B3F; 4B3G
• EC Number: 3.6.4.12; 3.6.4.13
• Pfam ID: PF13086 ; PF13087 ; PF01424 ; PF21138 ; PF01428
• Sequence:
  MASAAVESFVTKQLDLLELERDAEVEERRSWQENISLKELQSRGVCLLKLQVSSQRTGLY
  GRLLVTFEPRRYGSAAALPSNSFTSGDIVGLYDAANEGSQLATGILTRVTQKSVTVAFDE
  SHDFQLSLDRENSYRLLKLANDVTYRRLKKALIALKKYHSGPASSLIEVLFGRSAPSPAS
  EIHPLTFFNTCLDTSQKEAVLFALSQKELAIIHGPPGTGKTTTVVEIILQAVKQGLKVLC
  CAPSNIAVDNLVERLALCKQRILRLGHPARLLESIQQHSLDAVLARSDSAQIVADIRKDI
  DQVFVKNKKTQDKREKSNFRNEIKLLRKELKEREEAAMLESLTSANVVLATNTGASADGP
  LKLLPESYFDVVVIDECAQALEASCWIPLLKARKCILAGDHKQLPPTTVSHKAALAGLSL
  SLMERLAEEYGARVVRTLTVQYRMHQAIMRWASDTMYLGQLTAHSSVARHLLRDLPGVAA
  TEETGVPLLLVDTAGCGLFELEEEDEQSKGNPGEVRLVSLHIQALVDAGVPARDIAVVSP
  YNLQVDLLRQSLVHRHPELEIKSVDGFQGREKEAVILSFVRSNRKGEVGFLAEDRRINVA
  VTRARRHVAVICDSRTVNNHAFLKTLVEYFTQHGEVRTAFEYLDDIVPENYSHENSQGSS
  HAATKPQGPATSTRTGSQRQEGGQEAAAPARQGRKKPAGKSLASEAPSQPSLNGGSPEGV
  ESQDGVDHFRAMIVEFMASKKMQLEFPPSLNSHDRLRVHQIAEEHGLRHDSSGEGKRRFI
  TVSKRAPRPRAALGPPAGTGGPAPLQPVPPTPAQTEQPPREQRGPDQPDLRTLHLERLQR
  VRSAQGQPASKEQQASGQQKLPEKKKKKAKGHPATDLPTEEDFEALVSAAVKADNTCGFA
  KCTAGVTTLGQFCQLCSRRYCLSHHLPEIHGCGERARAHARQRISREGVLYAGSGTKNGS
  LDPAKRAQLQRRLDKKLSELSNQRTSRRKERGT
• Function: 5' to 3' helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction. Specific to 5'-phosphorylated single-stranded guanine-rich sequences. May play a role in RNA metabolism, ribosome biogenesis or initiation of translation. May play a role in regulation of transcription. Interacts with tRNA-Tyr.
• Tissue Specificity: Expressed in all tissues examined. Expressed in the developing and adult human brain, with highest expression in the cerebellum. Moderately expressed in fibroblasts.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive distal spinal muscular atrophy 1	DISA9P1I	Definitive	Autosomal recessive	[1]
Charcot-Marie-Tooth disease axonal type 2S	DISZWGPP	Definitive	Autosomal recessive	[2]
Hereditary peripheral neuropathy	DISSYRHC	Definitive	Autosomal recessive	[3]
Autonomic nervous system disorder	DIS6JLTA	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[6]
Charcot-Marie-Tooth disease type 2	DISR30O9	Strong	Genetic Variation	[7]
Congenital myopathy	DISLSK9G	Strong	Genetic Variation	[8]
Dysautonomia	DISF4MT6	Strong	Genetic Variation	[4]
Motor neurone disease	DISUHWUI	Strong	Genetic Variation	[9]
Motor peripheral neuropathy	DISVNBSJ	Strong	Biomarker	[10]
Myopathy	DISOWG27	Strong	Genetic Variation	[8]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[4]
Polyneuropathy	DISB9G3W	Strong	Genetic Variation	[11]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[12]
Respiratory failure	DISVMYJO	Strong	Genetic Variation	[13]
Spinal muscular atrophy	DISTLKOB	Strong	Genetic Variation	[14]
Spinal muscular atrophy, type 1	DISYCWUG	Strong	Biomarker	[15]
Peripheral sensory neuropathies	DISYWI6M	moderate	Biomarker	[16]

7 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 DNA-binding protein SMUBP-2 (IGHMBP2).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DNA-binding protein SMUBP-2 (IGHMBP2).	[18]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of DNA-binding protein SMUBP-2 (IGHMBP2).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DNA-binding protein SMUBP-2 (IGHMBP2).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA-binding protein SMUBP-2 (IGHMBP2).	[21]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of DNA-binding protein SMUBP-2 (IGHMBP2).	[23]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of DNA-binding protein SMUBP-2 (IGHMBP2).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA-binding protein SMUBP-2 (IGHMBP2).	[22]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] 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.
• [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] IGHMBP2 mutation associated with organ-specific autonomic dysfunction.Neuromuscul Disord. 2018 Dec;28(12):1012-1015. doi: 10.1016/j.nmd.2018.08.010. Epub 2018 Aug 29.
• [5] IGHMBP2 Thr671Ala polymorphism might be a modifier for the effects of cigarette smoking and PAH-DNA adducts to breast cancer risk.Breast Cancer Res Treat. 2006 Sep;99(1):1-7. doi: 10.1007/s10549-006-9174-3. Epub 2006 Jun 5.
• [6] Whole genome sequencing reveals novel IGHMBP2 variant leading to unique cryptic splice-site and Charcot-Marie-Tooth phenotype with early onset symptoms.Mol Genet Genomic Med. 2019 Jun;7(6):e00676. doi: 10.1002/mgg3.676. Epub 2019 Apr 25.
• [7] IGHMBP2-related clinical and genetic features in a cohort of Chinese Charcot-Marie-Tooth disease type 2 patients.Neuromuscul Disord. 2017 Feb;27(2):193-199. doi: 10.1016/j.nmd.2016.11.008. Epub 2016 Nov 18.
• [8] A congenital myopathy with diaphragmatic weakness not linked to the SMARD1 locus.Neuromuscul Disord. 2007 Feb;17(2):174-9. doi: 10.1016/j.nmd.2006.11.002. Epub 2007 Jan 22.
• [9] Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis. Neurology. 2014 Apr 15;82(15):1322-30. doi: 10.1212/WNL.0000000000000305. Epub 2014 Mar 19.
• [10] Diaphragmatic weakness with progressive sensory and motor polyneuropathy: case report of a neonatal IGHMBP2-related neuropathy.J Child Neurol. 2013 Jun;28(6):787-90. doi: 10.1177/0883073812450209. Epub 2012 Jul 12.
• [11] Clinical and molecular characteristics in three families with biallelic mutations in IGHMBP2.Neuromuscul Disord. 2016 Sep;26(9):570-5. doi: 10.1016/j.nmd.2016.06.457. Epub 2016 Jun 22.
• [12] Analysis of the transcriptional control region in progressive multifocal leukoencephalopathy.J Neurovirol. 2000 Oct;6(5):398-409. doi: 10.3109/13550280009018304.
• [13] Infantile spinal muscular atrophy with respiratory distress type I presenting without respiratory involvement: Novel mutations and review of the literature.Brain Dev. 2016 Aug;38(7):685-9. doi: 10.1016/j.braindev.2016.02.001. Epub 2016 Feb 24.
• [14] The wide spectrum of clinical phenotypes of spinal muscular atrophy with respiratory distress type 1: a systematic review.J Neurol Sci. 2014 Nov 15;346(1-2):35-42. doi: 10.1016/j.jns.2014.09.010. Epub 2014 Sep 16.
• [15] An atypical phenotype of a patient with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD 1).Eur J Med Genet. 2018 Oct;61(10):602-606. doi: 10.1016/j.ejmg.2018.04.001. Epub 2018 Apr 11.
• [16] Infantile spinal muscular atrophy with respiratory distress type I (SMARD 1): an atypical phenotype and review of the literature.Eur J Paediatr Neurol. 2012 Jan;16(1):90-4. doi: 10.1016/j.ejpn.2011.10.005. Epub 2011 Nov 18.
• [17] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [18] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [19] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [20] BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin Cancer Res. 2014 Feb 15;20(4):912-25.
• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [22] 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.
• [23] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [24] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.