Details of Drug Off-Target (DOT)

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

• DOT Name: Centrosomal protein of 41 kDa (CEP41)
• Synonyms: Cep41; Testis-specific gene A14 protein
• Gene Name: CEP41
• Related Disease:
  Joubert syndrome 15
  Autism
  Ewing sarcoma
  Joubert syndrome 1
  Neoplasm
  Schizophrenia
  Autism spectrum disorder
  Joubert syndrome
  Joubert syndrome with ocular defect
• UniProt ID: CEP41_HUMAN
• Pfam ID: PF00581
• Sequence:
  MSLRRHIGNPEYLMKRIPQNPRYQHIKSRLDTGNSMTKYTEKLEEIKKNYRYKKDELFKR
  LKVTTFAQLIIQVASLSDQTLEVTAEEIQRLEDNDSAASDPDAETTARTNGKGNPGEQSP
  SPEQFINNAGAGDSSRSTLQSVISGVGELDLDKGPVKKAEPHTKDKPYPDCPFLLLDVRD
  RDSYQQCHIVGAYSYPIATLSRTMNPYSNDILEYKNAHGKIIILYDDDERLASQAATTMC
  ERGFENLFMLSGGLKVLAQKFPEGLITGSLPASCQQALPPGSARKRSSPKGPPLPAENKW
  RFTPEDLKKIEYYLEEEQGPADHPSRLNQANSSGRESKVPGARSAQNLPGGGPASHSNPR
  SLSSGHLQGKPWK
• Function: Required during ciliogenesis for tubulin glutamylation in cilium. Probably acts by participating in the transport of TTLL6, a tubulin polyglutamylase, between the basal body and the cilium.
• Tissue Specificity: .Expressed in testis and fetal tissues.; [Isoform 3]: Expressed in testis and fetal tissues.
• Reactome Pathway:
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Joubert syndrome 15	DISJ7VDR	Definitive	Autosomal recessive	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Ewing sarcoma	DISQYLV3	Strong	Genetic Variation	[3]
Joubert syndrome 1	DISC9Q82	Strong	GermlineCausalMutation	[1]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[4]
Autism spectrum disorder	DISXK8NV	moderate	Genetic Variation	[5]
Joubert syndrome	DIS7P5CO	Supportive	Autosomal recessive	[1]
Joubert syndrome with ocular defect	DISDJVUI	Supportive	Autosomal recessive	[6]

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 Centrosomal protein of 41 kDa (CEP41).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Centrosomal protein of 41 kDa (CEP41).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Centrosomal protein of 41 kDa (CEP41).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Centrosomal protein of 41 kDa (CEP41).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Centrosomal protein of 41 kDa (CEP41).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Centrosomal protein of 41 kDa (CEP41).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Centrosomal protein of 41 kDa (CEP41).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Centrosomal protein of 41 kDa (CEP41).	[14]

References

• [1] CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium. Nat Genet. 2012 Jan 15;44(2):193-9. doi: 10.1038/ng.1078.
• [2] Methylation and expression analyses of the 7q autism susceptibility locus genes MEST , COPG2, and TSGA14 in human and anthropoid primate cortices.Cytogenet Genome Res. 2012;136(4):278-87. doi: 10.1159/000337298. Epub 2012 Mar 24.
• [3] Functional epigenetic approach identifies frequently methylated genes in Ewing sarcoma.Epigenetics. 2013 Nov;8(11):1198-204. doi: 10.4161/epi.26266. Epub 2013 Sep 4.
• [4] A molecular pathway analysis informs the genetic risk for arrhythmias during antipsychotic treatment.Int Clin Psychopharmacol. 2018 Jan;33(1):1-14. doi: 10.1097/YIC.0000000000000198.
• [5] Family-based exome sequencing and case-control analysis implicate CEP41 as an ASD gene.Transl Psychiatry. 2019 Jan 15;9(1):4. doi: 10.1038/s41398-018-0343-z.
• [6] Joubert Syndrome. 2003 Jul 9 [updated 2017 Jun 29]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [7] 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.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin Cancer Res. 2014 Feb 15;20(4):912-25.
• [13] 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.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.