Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ6XY2A)

• DOT Name: SH3 domain and tetratricopeptide repeat-containing protein 2 (SH3TC2)
• Gene Name: SH3TC2
• Related Disease:
  Charcot-Marie-Tooth disease type 4C
  Obsolete autosomal recessive hereditary demyelinating motor and sensory neuropathy
  Autism
  Charcot marie tooth disease
  Demyelinating polyneuropathy
  Hereditary motor and sensory neuropathy
  Peripheral neuropathy
  Movement disorder
  Partial trisomy of the long arm of chromosome 5
  Charcot-Marie-Tooth disease type 3
  Charcot-Marie-Tooth disease type 4
  Susceptibility to mononeuropathy of the median nerve, mild
• UniProt ID: S3TC2_HUMAN
• Pfam ID: PF00018
• Sequence:
  MGGCFCIPRERSLTRGPGKETPSKDPTVSSECIASSEYKEKCFLPQNINPDLTLSFCVKS
  RSRRCVNGPLQEAARRRLWALENEDQEVRMLFKDLSARLVSIQSQRAQFLITFKTMEEIW
  KFSTYLNLGYVSMCLEHLLFDHKYWLNCILVEDTEIQVSVDDKHLETIYLGLLIQEGHFF
  CRALCSVTPPAEKEGECLTLCKNELISVKMAEAGSELEGVSLVTGQRGLVLVSALEPLPL
  PFHQWFLKNYPGSCGLSRKRDWTGSYQIGRGRCKALTGYEPGEKDELNFYQGESIEIIGF
  VIPGLQWFIGKSTSSGQVGFVPTRNIDPDSYSPMSRNSAFLSDEERCSLLALGSDKQTEC
  SSFLHTLARTDITSVYRLSGFESIQNPPNDLSASQPEGFKEVRPGRAWEEHQAVGSRQSS
  SSEDSSLEEELLSATSDSYRLPEPDDLDDPELLMDLSTGQEEEAENFAPILAFLDHEGYA
  DHFKSLYDFSFSFLTSSFYSFSEEDEFVAYLEASRKWAKKSHMTWAHARLCFLLGRLSIR
  KVKLSQARVYFEEAIHILNGAFEDLSLVATLYINLAAIYLKQRLRHKGSALLEKAGALLA
  CLPDRESSAKHELDVVAYVLRQGIVVGSSPLEARACFLAIRLLLSLGRHEEVLPFAERLQ
  LLSGHPPASEAVASVLSFLYDKKYLPHLAVASVQQHGIQSAQGMSLPIWQVHLVLQNTTK
  LLGFPSPGWGEVSALACPMLRQALAACEELADRSTQRALCLILSKVYLEHRSPDGAIHYL
  SQALVLGQLLGEQESFESSLCLAWAYLLASQAKKALDVLEPLLCSLKETESLTQRGVIYN
  LLGLALQGEGRVNRAAKSYLRALNRAQEVGDVHNQAVAMANLGHLSLKSWAQHPARNYLL
  QAVRLYCELQASKETDMELVQVFLWLAQVLVSGHQLTHGLLCYEMALLFGLRHRHLKSQL
  QATKSLCHFYSSVSPNPEACITYHEHWLALAQQLRDREMEGRLLESLGQLYRNLNTARSL
  RRSLTCIKESLRIFIDLGETDKAAEAWLGAGRLHYLMQEDELVELCLQAAIQTALKSEEP
  LLALKLYEEAGDVFFNGTRHRHHAVEYYRAGAVPLARRLKAVRTELRIFNKLTELQISLE
  GYEKALEFATLAARLSTVTGDQRQELVAFHRLATVYYSLHMYEMAEDCYLKTLSLCPPWL
  QSPKEALYYAKVYYRLGRLTFCQLKDAHDATEYFLLALAAAVLLGDEELQDTIRSRLDNI
  CQSPLWHSRPSGCSSERARWLSGGGLAL
• Tissue Specificity: Strongly expressed in brain and spinal cord. Expressed at equal level in spinal cord and sciatic nerve. Weakly expressed in striated muscle.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-Marie-Tooth disease type 4C	DIS0SF7F	Definitive	Autosomal recessive	[1]
Obsolete autosomal recessive hereditary demyelinating motor and sensory neuropathy	DISB5XCQ	Definitive	Autosomal recessive	[2]
Autism	DISV4V1Z	Strong	Genetic Variation	[3]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[4]
Demyelinating polyneuropathy	DIS7IO4W	Strong	Genetic Variation	[4]
Hereditary motor and sensory neuropathy	DISR0X2K	Strong	Genetic Variation	[5]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[6]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[7]
Partial trisomy of the long arm of chromosome 5	DISFHG81	moderate	Genetic Variation	[8]
Charcot-Marie-Tooth disease type 3	DIS6DQK1	Limited	Biomarker	[9]
Charcot-Marie-Tooth disease type 4	DISM8IZN	Limited	CausalMutation	[10]
Susceptibility to mononeuropathy of the median nerve, mild	DISN8VA7	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of SH3 domain and tetratricopeptide repeat-containing protein 2 (SH3TC2).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of SH3 domain and tetratricopeptide repeat-containing protein 2 (SH3TC2).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of SH3 domain and tetratricopeptide repeat-containing protein 2 (SH3TC2).	[13]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of SH3 domain and tetratricopeptide repeat-containing protein 2 (SH3TC2).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of SH3 domain and tetratricopeptide repeat-containing protein 2 (SH3TC2).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of SH3 domain and tetratricopeptide repeat-containing protein 2 (SH3TC2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of SH3 domain and tetratricopeptide repeat-containing protein 2 (SH3TC2).	[18]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of SH3 domain and tetratricopeptide repeat-containing protein 2 (SH3TC2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of SH3 domain and tetratricopeptide repeat-containing protein 2 (SH3TC2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of SH3 domain and tetratricopeptide repeat-containing protein 2 (SH3TC2).	[19]

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] 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.
• [3] Characterization of a de novo translocation t(5;18)(q33.1;q12.1) in an autistic boy identifies a breakpoint close to SH3TC2, ADRB2, and HTR4 on 5q, and within the desmocollin gene cluster on 18q.Am J Med Genet B Neuropsychiatr Genet. 2009 Sep 5;150B(6):817-26. doi: 10.1002/ajmg.b.30903.
• [4] Mutational screening of the SH3TC2 gene in Greek patients with suspected demyelinating recessive Charcot-Marie-Tooth disease reveals a varied and unusual phenotypic spectrum.J Peripher Nerv Syst. 2019 Mar;24(1):125-130. doi: 10.1111/jns.12305. Epub 2019 Feb 6.
• [5] Genetics of the Charcot-Marie-Tooth disease in the Spanish Gypsy population: the hereditary motor and sensory neuropathy-Russe in depth.Clin Genet. 2013 Jun;83(6):565-70. doi: 10.1111/cge.12015. Epub 2012 Oct 10.
• [6] Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathy.Brain. 2019 May 1;142(5):1227-1241. doi: 10.1093/brain/awz064.
• [7] High frequency of SH3TC2 mutations in Czech HMSN I patients.Clin Genet. 2011 Oct;80(4):334-45. doi: 10.1111/j.1399-0004.2011.01640.x. Epub 2011 Mar 1.
• [8] Genome-wide analysis of copy number changes and loss of heterozygosity in myelodysplastic syndrome with del(5q) using high-density single nucleotide polymorphism arrays.Haematologica. 2008 Jul;93(7):994-1000. doi: 10.3324/haematol.12603. Epub 2008 May 27.
• [9] SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system.Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17528-33. doi: 10.1073/pnas.0905523106. Epub 2009 Sep 29.
• [10] Audiological Findings in Charcot-Marie-Tooth Disease Type 4C.J Int Adv Otol. 2017 Apr;13(1):93-99. doi: 10.5152/iao.2017.3379.
• [11] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [12] Research resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. Mol Endocrinol. 2014 Dec;28(12):2072-81.
• [13] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [14] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [18] 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.
• [19] 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.
• [20] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.