Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLC8K6B)

• DOT Name: Cytoplasmic dynein 2 heavy chain 1 (DYNC2H1)
• Synonyms: Cytoplasmic dynein 2 heavy chain; Dynein cytoplasmic heavy chain 2; Dynein heavy chain 11; hDHC11; Dynein heavy chain isotype 1B
• Gene Name: DYNC2H1
• Related Disease:
  Asphyxiating thoracic dystrophy 3
  Tuberculosis
  Ataxia-telangiectasia
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Ciliopathy
  Moyamoya disease
  Pancreatic cancer
  Short rib-polydactyly syndrome
  Short-rib thoracic dysplasia 6 with or without polydactyly
  Short-rib thoracic dysplasia 9 with or without polydactyly
  Skeletal system disorder
  Jeune syndrome
  Obsolete short rib-polydactyly syndrome, Verma-Naumoff type
  Short rib-polydactyly syndrome, Majewski type
  Glioma
  Adult glioblastoma
  Glioblastoma multiforme
  Polydactyly
• UniProt ID: DYHC2_HUMAN
• PDB ID: 4RH7
• Pfam ID: PF12774 ; PF12775 ; PF12780 ; PF12781 ; PF18198 ; PF08385 ; PF08393 ; PF21264 ; PF18199 ; PF03028 ; PF12777
• Sequence:
  MANGTADVRKLFIFTTTQNYFGLMSELWDQPLLCNCLEINNFLDDGNQMLLRVQRSDAGI
  SFSNTIEFGDTKDKVLVFFKLRPEVITDENLHDNILVSSMLESPISSLYQAVRQVFAPML
  LKDQEWSRNFDPKLQNLLSELEAGLGIVLRRSDTNLTKLKFKEDDTRGILTPSDEFQFWI
  EQAHRGNKQISKERANYFKELFETIAREFYNLDSLSLLEVVDLVETTQDVVDDVWRQTEH
  DHYPESRMLHLLDIIGGSFGRFVQKKLGTLNLWEDPYYLVKESLKAGISICEQWVIVCNH
  LTGQVWQRYVPHPWKNEKYFPETLDKLGKRLEEVLAIRTIHEKFLYFLPASEEKIICLTR
  VFEPFTGLNPVQYNPYTEPLWKAAVSQYEKIIAPAEQKIAGKLKNYISEIQDSPQQLLQA
  FLKYKELVKRPTISKELMLERETLLARLVDSIKDFRLDFENRCRGIPGDASGPLSGKNLS
  EVVNSIVWVRQLELKVDDTIKIAEALLSDLPGFRCFHQSAKDLLDQLKLYEQEQFDDWSR
  DIQSGLSDSRSGLCIEASSRIMELDSNDGLLKVHYSDRLVILLREVRQLSALGFVIPAKI
  QQVANIAQKFCKQAIILKQVAHFYNSIDQQMIQSQRPMMLQSALAFEQIIKNSKAGSGGK
  SQITWDNPKELEGYIQKLQNAAERLATENRKLRKWHTTFCEKVVVLMNIDLLRQQQRWKD
  GLQELRTGLATVEAQGFQASDMHAWKQHWNHQLYKALEHQYQMGLEALNENLPEINIDLT
  YKQGRLQFRPPFEEIRAKYYREMKRFIGIPNQFKGVGEAGDESIFSIMIDRNASGFLTIF
  SKAEDLFRRLSAVLHQHKEWIVIGQVDMEALVEKHLFTVHDWEKNFKALKIKGKEVERLP
  SAVKVDCLNINCNPVKTVIDDLIQKLFDLLVLSLKKSIQAHLHEIDTFVTEAMEVLTIMP
  QSVEEIGDANLQYSKLQERKPEILPLFQEAEDKNRLLRTVAGGGLETISNLKAKWDKFEL
  MMESHQLMIKDQIEVMKGNVKSRLQIYYQELEKFKARWDQLKPGDDVIETGQHNTLDKSA
  KLIKEKKIEFDDLEVTRKKLVDDCHHFRLEEPNFSLASSISKDIESCAQIWAFYEEFQQG
  FQEMANEDWITFRTKTYLFEEFLMNWHDRLRKVEEHSVMTVKLQSEVDKYKIVIPILKYV
  RGEHLSPDHWLDLFRLLGLPRGTSLEKLLFGDLLRVADTIVAKAADLKDLNSRAQGEVTI
  REALRELDLWGVGAVFTLIDYEDSQSRTMKLIKDWKDIVNQVGDNRCLLQSLKDSPYYKG
  FEDKVSIWERKLAELDEYLQNLNHIQRKWVYLEPIFGRGALPKEQTRFNRVDEDFRSIMT
  DIKKDNRVTTLTTHAGIRNSLLTILDQLQRCQKSLNEFLEEKRSAFPRFYFIGDDDLLEI
  LGQSTNPSVIQSHLKKLFAGINSVCFDEKSKHITAMKSLEGEVVPFKNKVPLSNNVETWL
  NDLALEMKKTLEQLLKECVTTGRSSQGAVDPSLFPSQILCLAEQIKFTEDVENAIKDHSL
  HQIETQLVNKLEQYTNIDTSSEDPGNTESGILELKLKALILDIIHNIDVVKQLNQIQVHT
  TEDWAWKKQLRFYMKSDHTCCVQMVDSEFQYTYEYQGNASKLVYTPLTDKCYLTLTQAMK
  MGLGGNPYGPAGTGKTESVKALGGLLGRQVLVFNCDEGIDVKSMGRIFVGLVKCGAWGCF
  DEFNRLEESVLSAVSMQIQTIQDALKNHRTVCELLGKEVEVNSNSGIFITMNPAGKGYGG
  RQKLPDNLKQLFRPVAMSHPDNELIAEVILYSEGFKDAKVLSRKLVAIFNLSRELLTPQQ
  HYDWGLRALKTVLRGSGNLLRQLNKSGTTQNANESHIVVQALRLNTMSKFTFTDCTRFDA
  LIKDVFPGIELKEVEYDELSAALKQVFEEANYEIIPNQIKKALELYEQLCQRMGVVIVGP
  SGAGKSTLWRMLRAALCKTGKVVKQYTMNPKAMPRYQLLGHIDMDTREWSDGVLTNSARQ
  VVREPQDVSSWIICDGDIDPEWIESLNSVLDDNRLLTMPSGERIQFGPNVNFVFETHDLS
  CASPATISRMGMIFLSDEETDLNSLIKSWLRNQPAEYRNNLENWIGDYFEKALQWVLKQN
  DYVVETSLVGTVMNGLSHLHGCRDHDEFIINLIRGLGGNLNMKSRLEFTKEVFHWARESP
  PDFHKPMDTYYDSTRGRLATYVLKKPEDLTADDFSNGLTLPVIQTPDMQRGLDYFKPWLS
  SDTKQPFILVGPEGCGKGMLLRYAFSQLRSTQIATVHCSAQTTSRHLLQKLSQTCMVIST
  NTGRVYRPKDCERLVLYLKDINLPKLDKWGTSTLVAFLQQVLTYQGFYDENLEWVGLENI
  QIVASMSAGGRLGRHKLTTRFTSIVRLCSIDYPEREQLQTIYGAYLEPVLHKNLKNHSIW
  GSSSKIYLLAGSMVQVYEQVRAKFTVDDYSHYFFTPCILTQWVLGLFRYDLEGGSSNHPL
  DYVLEIVAYEARRLFRDKIVGAKELHLFDIILTSVFQGDWGSDILDNMSDSFYVTWGARH
  NSGARAAPGQPLPPHGKPLGKLNSTDLKDVIKKGLIHYGRDNQNLDILLFHEVLEYMSRI
  DRVLSFPGGSLLLAGRSGVGRRTITSLVSHMHGAVLFSPKISRGYELKQFKNDLKHVLQL
  AGIEAQQVVLLLEDYQFVHPTFLEMINSLLSSGEVPGLYTLEELEPLLLPLKDQASQDGF
  FGPVFNYFTYRIQQNLHIVLIMDSANSNFMINCESNPALHKKCQVLWMEGWSNSSMKKIP
  EMLFSETGGGEKYNDKKRKEEKKKNSVDPDFLKSFLLIHESCKAYGATPSRYMTFLHVYS
  AISSSKKKELLKRQSHLQAGVSKLNEAKALVDELNRKAGEQSVLLKTKQDEADAALQMIT
  VSMQDASEQKTELERLKHRIAEEVVKIEERKNKIDDELKEVQPLVNEAKLAVGNIKPESL
  SEIRSLRMPPDVIRDILEGVLRLMGIFDTSWVSMKSFLAKRGVREDIATFDARNISKEIR
  ESVEELLFKNKGSFDPKNAKRASTAAAPLAAWVKANIQYSHVLERIHPLETEQAGLESNL
  KKTEDRKRKLEELLNSVGQKVSELKEKFQSRTSEAAKLEAEVSKAQETIKAAEVLINQLD
  REHKRWNAQVVEITEELATLPKRAQLAAAFITYLSAAPESLRKTCLEEWTKSAGLEKFDL
  RRFLCTESEQLIWKSEGLPSDDLSIENALVILQSRVCPFLIDPSSQATEWLKTHLKDSRL
  EVINQQDSNFITALELAVRFGKTLIIQEMDGVEPVLYPLLRRDLVAQGPRYVVQIGDKII
  DYNEEFRLFLSTRNPNPFIPPDAASIVTEVNFTTTRSGLRGQLLALTIQHEKPDLEEQKT
  KLLQQEEDKKIQLAKLEESLLETLATSQGNILENKDLIESLNQTKASSALIQESLKESYK
  LQISLDQERDAYLPLAESASKMYFIISDLSKINNMYRFSLAAFLRLFQRALQNKQDSENT
  EQRIQSLISSLQHMVYEYICRCLFKADQLMFALHFVRGMHPELFQENEWDTFTGVVVGDM
  LRKADSQQKIRDQLPSWIDQERSWAVATLKIALPSLYQTLCFEDAALWRTYYNNSMCEQE
  FPSILAKKVSLFQQILVVQALRPDRLQSAMALFACKTLGLKEVSPLPLNLKRLYKETLEI
  EPILIIISPGADPSQELQELANAERSGECYHQVAMGQGQADLAIQMLKECARNGDWLCLK
  NLHLVVSWLPVLEKELNTLQPKDTFRLWLTAEVHPNFTPILLQSSLKITYESPPGLKKNL
  MRTYESWTPEQISKKDNTHRAHALFSLAWFHAACQERRNYIPQGWTKFYEFSLSDLRAGY
  NIIDRLFDGAKDVQWEFVHGLLENAIYGGRIDNYFDLRVLQSYLKQFFNSSVIDVFNQRN
  KKSIFPYSVSLPQSCSILDYRAVIEKIPEDDKPSFFGLPANIARSSQRMISSQVISQLRI
  LGRSITAGSKFDREIWSNELSPVLNLWKKLNQNSNLIHQKVPPPNDRQGSPILSFIILEQ
  FNAIRLVQSVHQSLAALSKVIRGTTLLSSEVQKLASALLNQKCPLAWQSKWEGPEDPLQY
  LRGLVARALAIQNWVDKAEKQALLSETLDLSELFHPDTFLNALRQETARAVGRSVDSLKF
  VASWKGRLQEAKLQIKISGLLLEGCSFDGNQLSENQLDSPSVSSVLPCFMGWIPQDACGP
  YSPDECISLPVYTSAERDRVVTNIDVPCGGNQDQWIQCGAALFLKNQ
• Function: May function as a motor for intraflagellar retrograde transport. Functions in cilia biogenesis. May play a role in transport between endoplasmic reticulum and Golgi or organization of the Golgi in cells.
• KEGG Pathway:
  Phagosome (hsa04145)
  Motor proteins (hsa04814)
  Vasopressin-regulated water reabsorption (hsa04962)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  Intraflagellar transport (R-HSA-5620924)
  Hedgehog 'off' state (R-HSA-5610787)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asphyxiating thoracic dystrophy 3	DISFN8TK	Definitive	Autosomal recessive	[1]
Tuberculosis	DIS2YIMD	Definitive	Genetic Variation	[2]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[5]
Moyamoya disease	DISO62CA	Strong	Biomarker	[6]
Pancreatic cancer	DISJC981	Strong	Biomarker	[7]
Short rib-polydactyly syndrome	DISY2RES	Strong	Genetic Variation	[8]
Short-rib thoracic dysplasia 6 with or without polydactyly	DISEN8P1	Strong	Biomarker	[9]
Short-rib thoracic dysplasia 9 with or without polydactyly	DISU7SPS	Strong	Biomarker	[10]
Skeletal system disorder	DIS5PU87	moderate	Genetic Variation	[8]
Jeune syndrome	DISLC357	Supportive	Autosomal recessive	[11]
Obsolete short rib-polydactyly syndrome, Verma-Naumoff type	DISS6UQH	Supportive	Autosomal recessive	[12]
Short rib-polydactyly syndrome, Majewski type	DIS0GCAA	Supportive	Autosomal recessive	[12]
Glioma	DIS5RPEH	Disputed	Biomarker	[13]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[14]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[14]
Polydactyly	DIS25BMZ	Limited	Biomarker	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cytoplasmic dynein 2 heavy chain 1 (DYNC2H1).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytoplasmic dynein 2 heavy chain 1 (DYNC2H1).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cytoplasmic dynein 2 heavy chain 1 (DYNC2H1).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Cytoplasmic dynein 2 heavy chain 1 (DYNC2H1).	[19]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Cytoplasmic dynein 2 heavy chain 1 (DYNC2H1).	[20]
Fenfluramine	DM0762O	Phase 3	Fenfluramine increases the expression of Cytoplasmic dynein 2 heavy chain 1 (DYNC2H1).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytoplasmic dynein 2 heavy chain 1 (DYNC2H1).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cytoplasmic dynein 2 heavy chain 1 (DYNC2H1).	[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 Cytoplasmic dynein 2 heavy chain 1 (DYNC2H1).	[23]

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] Genome-wide association study of ancestry-specific TB risk in the South African Coloured population.Hum Mol Genet. 2014 Feb 1;23(3):796-809. doi: 10.1093/hmg/ddt462. Epub 2013 Sep 20.
• [3] Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families. J Med Genet. 2013 Feb;50(2):91-8. doi: 10.1136/jmedgenet-2012-101282.
• [4] Combined deletion of Pten and p53 in mammary epithelium accelerates triple-negative breast cancer with dependency on eEF2K.EMBO Mol Med. 2014 Dec;6(12):1542-60. doi: 10.15252/emmm.201404402.
• [5] DYNC2H1 mutation causes Jeune syndrome and recurrent lung infections associated with ciliopathy.Clin Respir J. 2018 Mar;12(3):1017-1020. doi: 10.1111/crj.12620. Epub 2017 Mar 12.
• [6] Exome sequencing in seven families and gene-based association studies indicate genetic heterogeneity and suggest possible candidates for fibromuscular dysplasia.J Hypertens. 2015 Sep;33(9):1802-10; discussion 1810. doi: 10.1097/HJH.0000000000000625.
• [7] Linc-DYNC2H1-4 promotes EMT and CSC phenotypes by acting as a sponge of miR-145 in pancreatic cancer cells.Cell Death Dis. 2017 Jul 13;8(7):e2924. doi: 10.1038/cddis.2017.311.
• [8] Targeted gene panel sequencing prenatally detects two novel mutations of DYNC2H1 in a fetus with increased biparietal diameter and polyhydramnios.Birth Defects Res. 2018 Mar 1;110(4):364-371. doi: 10.1002/bdr2.1146. Epub 2018 Jan 23.
• [9] NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases.J Med Genet. 2012 Apr;49(4):227-33. doi: 10.1136/jmedgenet-2011-100717.
• [10] Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans. Am J Hum Genet. 2013 Nov 7;93(5):915-25. doi: 10.1016/j.ajhg.2013.09.012. Epub 2013 Oct 17.
• [11] Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement. J Med Genet. 2013 May;50(5):309-23. doi: 10.1136/jmedgenet-2012-101284. Epub 2013 Mar 1.
• [12] Ciliary disorder of the skeleton. Am J Med Genet C Semin Med Genet. 2012 Aug 15;160C(3):165-74. doi: 10.1002/ajmg.c.31336. Epub 2012 Jul 12.
• [13] Identification of histological markers for malignant glioma by genome-wide expression analysis: dynein, alpha-PIX and sorcin.Acta Neuropathol. 2006 Jan;111(1):29-38. doi: 10.1007/s00401-005-1085-6. Epub 2005 Nov 30.
• [14] Acquired temozolomide resistance in MGMT-deficient glioblastoma cells is associated with regulation of DNA repair by DHC2.Brain. 2019 Aug 1;142(8):2352-2366. doi: 10.1093/brain/awz202.
• [15] Prenatal diagnosis of short-rib polydactyly syndrome type III or short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3) associated with compound heterozygous mutations in DYNC2H1 in afetus.Taiwan J Obstet Gynecol. 2018 Feb;57(1):123-127. doi: 10.1016/j.tjog.2017.12.021.
• [16] 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.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [20] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [21] Fenfluramine-induced gene dysregulation in human pulmonary artery smooth muscle and endothelial cells. Pulm Circ. 2011 Jul-Sep;1(3):405-18. doi: 10.4103/2045-8932.87310.
• [22] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [23] 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.
• [24] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.