Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFTWIT7)

• DOT Name: Cytoplasmic dynein 2 intermediate chain 1 (DYNC2I1)
• Synonyms: Dynein 2 intermediate chain 1; WD repeat-containing protein 60
• Gene Name: DYNC2I1
• Related Disease:
  Short-rib thoracic dysplasia 8 with or without polydactyly
  Jeune syndrome
  Obsolete short rib-polydactyly syndrome, Verma-Naumoff type
• UniProt ID: DC2I1_HUMAN
• PDB ID: 6RLB; 6SC2
• Sequence:
  MEPGKRRTKDDTWKADDLRKHLWAIQSGGSKEERKHREKKLRKESEMDLPEHKEPRCRDP
  DQDARSRDRVAEVHTAKESPRGERDRDRQRERRRDAKDREKEKLKEKHREAEKSHSRGKD
  REKEKDRRARKEELRQTVAHHNLLGQETRDRQLLERAERKGRSVSKVRSEEKDEDSERGD
  EDRERRYRERKLQYGDSKDNPLKYWLYKEEGERRHRKPREPDRDNKHREKSSTREKREKY
  SKEKSNSFSDKGEERHKEKRHKEGFHFDDERHQSNVDRKEKSAKDEPRKRESQNGEHRNR
  GASSKRDGTSSQHAENLVRNHGKDKDSRRKHGHEEGSSVWWKLDQRPGGEETVEIEKEET
  DLENARADAYTASCEDDFEDYEDDFEVCDGDDDESSNEPESREKLEELPLAQKKEIQEIQ
  RAINAENERIGELSLKLFQKRGRTEFEKEPRTDTNSSPSRASVCGIFVDFASASHRQKSR
  TQALKQKMRSTKLLRLIDLDFSFTFSLLDLPPVNEYDMYIRNFGKKNTKQAYVQCNEDNV
  ERDIQTEEIETREVWTQHPGESTVVSGGSEQRDTSDAVVMPKIDTPRLCSFLRAACQVMA
  VLLEEDRLAAEPSWNLRAQDRALYFSDSSSQLNTSLPFLQNRKVSSLHTSRVQRQMVVSV
  HDLPEKSFVPLLDSKYVLCVWDIWQPSGPQKVLICESQVTCCCLSPLKAFLLFAGTAHGS
  VVVWDLREDSRLHYSVTLSDGFWTFRTATFSTDGILTSVNHRSPLQAVEPISTSVHKKQS
  FVLSPFSTQEEMSGLSFHIASLDESGVLNVWVVVELPKADIAGSISDLGLMPGGRVKLVH
  SALIQLGDSLSHKGNEFWGTTQTLNVKFLPSDPNHFIIGTDMGLISHGTRQDLRVAPKLF
  KPQQHGIRPVKVNVIDFSPFGEPIFLAGCSDGSIRLHQLSSAFPLLQWDSSTDSHAVTGL
  QWSPTRPAVFLVQDDTSNIYIWDLLQSDLGPVAKQQVSPNRLVAMAAVGEPEKAGGSFLA
  LVLARASGSIDIQHLKRRWAAPEVDECNRLRLLLQEALWPEGKLHK
• Function: Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 2 complex (dynein-2 complex), a motor protein complex that drives the movement of cargos along microtubules within cilia and flagella in concert with the intraflagellar transport (IFT) system. DYNC2I1 plays a major role in retrograde ciliary protein trafficking in cilia and flagella. Requires also to maintain a functional transition zone.
• Tissue Specificity: Expressed in chondrocytes (at protein level).
• Reactome Pathway: Intraflagellar transport (R-HSA-5620924)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Short-rib thoracic dysplasia 8 with or without polydactyly	DISGEBJT	Strong	Autosomal recessive	[1]
Jeune syndrome	DISLC357	Supportive	Autosomal recessive	[2]
Obsolete short rib-polydactyly syndrome, Verma-Naumoff type	DISS6UQH	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Cytoplasmic dynein 2 intermediate chain 1 (DYNC2I1).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cytoplasmic dynein 2 intermediate chain 1 (DYNC2I1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Cytoplasmic dynein 2 intermediate chain 1 (DYNC2I1).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cytoplasmic dynein 2 intermediate chain 1 (DYNC2I1).	[6]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cytoplasmic dynein 2 intermediate chain 1 (DYNC2I1).	[7]

References

• [1] 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.
• [2] Short-rib polydactyly and Jeune syndromes are caused by mutations in WDR60. Am J Hum Genet. 2013 Sep 5;93(3):515-23. doi: 10.1016/j.ajhg.2013.06.022. Epub 2013 Aug 1.
• [3] 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.
• [4] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [5] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [6] 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.
• [7] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.