Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC21RUS)

• DOT Name: Dynein axonemal heavy chain 5 (DNAH5)
• Synonyms: Axonemal beta dynein heavy chain 5; Ciliary dynein heavy chain 5
• Gene Name: DNAH5
• Related Disease:
  Nasal polyp
  Primary ciliary dyskinesia 3
  Scleroderma
  Systemic sclerosis
  Advanced cancer
  Bronchiectasis
  Craniosynostosis
  Cystic fibrosis
  Fleck corneal dystrophy
  Hydrocephalus
  Inflammatory bowel disease
  Lung squamous cell carcinoma
  Male infertility
  Otitis media
  Pancreatic cancer
  Primary ciliary dyskinesia 1
  Prostate cancer
  Prostate carcinoma
  Situs inversus
  Tetralogy of fallot
  Urinary tract infection
  Asthma
  Castration-resistant prostate carcinoma
  Primary ciliary dyskinesia
  Neoplasm
  Chronic obstructive pulmonary disease
  Venous thromboembolism
• UniProt ID: DYH5_HUMAN
• PDB ID: 8J07
• Pfam ID: PF12774 ; PF12775 ; PF12780 ; PF12781 ; PF17857 ; PF18198 ; PF08385 ; PF08393 ; PF17852 ; PF18199 ; PF03028 ; PF12777
• Sequence:
  MFRIGRRQLWKHSVTRVLTQRLKGEKEAKRALLDARHNYLFAIVASCLDLNKTEVEDAIL
  EGNQIERIDQLFAVGGLRHLMFYYQDVEEAETGQLGSLGGVNLVSGKIKKPKVFVTEGND
  VALTGVCVFFIRTDPSKAITPDNIHQEVSFNMLDAADGGLLNSVRRLLSDIFIPALRATS
  HGWGELEGLQDAANIRQEFLSSLEGFVNVLSGAQESLKEKVNLRKCDILELKTLKEPTDY
  LTLANNPETLGKIEDCMKVWIKQTEQVLAENNQLLKEADDVGPRAELEHWKKRLSKFNYL
  LEQLKSPDVKAVLAVLAAAKSKLLKTWREMDIRITDATNEAKDNVKYLYTLEKCCDPLYS
  SDPLSMMDAIPTLINAIKMIYSISHYYNTSEKITSLFVKVTNQIISACKAYITNNGTASI
  WNQPQDVVEEKILSAIKLKQEYQLCFHKTKQKLKQNPNAKQFDFSEMYIFGKFETFHRRL
  AKIIDIFTTLKTYSVLQDSTIEGLEDMATKYQGIVATIKKKEYNFLDQRKMDFDQDYEEF
  CKQTNDLHNELRKFMDVTFAKIQNTNQALRMLKKFERLNIPNLGIDDKYQLILENYGADI
  DMISKLYTKQKYDPPLARNQPPIAGKILWARQLFHRIQQPMQLFQQHPAVLSTAEAKPII
  RSYNRMAKVLLEFEVLFHRAWLRQIEEIHVGLEASLLVKAPGTGELFVNFDPQILILFRE
  TECMAQMGLEVSPLATSLFQKRDRYKRNFSNMKMMLAEYQRVKSKIPAAIEQLIVPHLAK
  VDEALQPGLAALTWTSLNIEAYLENTFAKIKDLELLLDRVNDLIEFRIDAILEEMSSTPL
  CQLPQEEPLTCEEFLQMTKDLCVNGAQILHFKSSLVEEAVNELVNMLLDVEVLSEEESEK
  ISNENSVNYKNESSAKREEGNFDTLTSSINARANALLLTTVTRKKKETEMLGEEARELLS
  HFNHQNMDALLKVTRNTLEAIRKRIHSSHTINFRDSNSASNMKQNSLPIFRASVTLAIPN
  IVMAPALEDVQQTLNKAVECIISVPKGVRQWSSELLSKKKIQERKMAALQSNEDSDSDVE
  MGENELQDTLEIASVNLPIPVQTKNYYKNVSENKEIVKLVSVLSTIINSTKKEVITSMDC
  FKRYNHIWQKGKEEAIKTFITQSPLLSEFESQILYFQNLEQEINAEPEYVCVGSIALYTA
  DLKFALTAETKAWMVVIGRHCNKKYRSEMENIFMLIEEFNKKLNRPIKDLDDIRIAMAAL
  KEIREEQISIDFQVGPIEESYALLNRYGLLIAREEIDKVDTLHYAWEKLLARAGEVQNKL
  VSLQPSFKKELISAVEVFLQDCHQFYLDYDLNGPMASGLKPQEASDRLIMFQNQFDNIYR
  KYITYTGGEELFGLPATQYPQLLEIKKQLNLLQKIYTLYNSVIETVNSYYDILWSEVNIE
  KINNELLEFQNRCRKLPRALKDWQAFLDLKKIIDDFSECCPLLEYMASKAMMERHWERIT
  TLTGHSLDVGNESFKLRNIMEAPLLKYKEEIEDICISAVKERDIEQKLKQVINEWDNKTF
  TFGSFKTRGELLLRGDSTSEIIANMEDSLMLLGSLLSNRYNMPFKAQIQKWVQYLSNSTD
  IIESWMTVQNLWIYLEAVFVGGDIAKQLPKEAKRFSNIDKSWVKIMTRAHEVPSVVQCCV
  GDETLGQLLPHLLDQLEICQKSLTGYLEKKRLCFPRFFFVSDPALLEILGQASDSHTIQA
  HLLNVFDNIKSVKFHEKIYDRILSISSQEGETIELDKPVMAEGNVEVWLNSLLEESQSSL
  HLVIRQAAANIQETGFQLTEFLSSFPAQVGLLGIQMIWTRDSEEALRNAKFDKKIMQKTN
  QAFLELLNTLIDVTTRDLSSTERVKYETLITIHVHQRDIFDDLCHMHIKSPMDFEWLKQC
  RFYFNEDSDKMMIHITDVAFIYQNEFLGCTDRLVITPLTDRCYITLAQALGMSMGGAPAG
  PAGTGKTETTKDMGRCLGKYVVVFNCSDQMDFRGLGRIFKGLAQSGSWGCFDEFNRIDLP
  VLSVAAQQISIILTCKKEHKKSFIFTDGDNVTMNPEFGLFLTMNPGYAGRQELPENLKIN
  FRSVAMMVPDRQIIIRVKLASCGFIDNVVLARKFFTLYKLCEEQLSKQVHYDFGLRNILS
  VLRTLGAAKRANPMDTESTIVMRVLRDMNLSKLIDEDEPLFLSLIEDLFPNILLDKAGYP
  ELEAAISRQVEEAGLINHPPWKLKVIQLFETQRVRHGMMTLGPSGAGKTTCIHTLMRAMT
  DCGKPHREMRMNPKAITAPQMFGRLDVATNDWTDGIFSTLWRKTLRAKKGEHIWIILDGP
  VDAIWIENLNSVLDDNKTLTLANGDRIPMAPNCKIIFEPHNIDNASPATVSRNGMVFMSS
  SILDWSPILEGFLKKRSPQEAEILRQLYTESFPDLYRFCIQNLEYKMEVLEAFVITQSIN
  MLQGLIPLKEQGGEVSQAHLGRLFVFALLWSAGAALELDGRRRLELWLRSRPTGTLELPP
  PAGPGDTAFDYYVAPDGTWTHWNTRTQEYLYPSDTTPEYGSILVPNVDNVRTDFLIQTIA
  KQGKAVLLIGEQGTAKTVIIKGFMSKYDPECHMIKSLNFSSATTPLMFQRTIESYVDKRM
  GTTYGPPAGKKMTVFIDDVNMPIINEWGDQVTNEIVRQLMEQNGFYNLEKPGEFTSIVDI
  QFLAAMIHPGGGRNDIPQRLKRQFSIFNCTLPSEASVDKIFGVIGVGHYCTQRGFSEEVR
  DSVTKLVPLTRRLWQMTKIKMLPTPAKFHYVFNLRDLSRVWQGMLNTTSEVIKEPNDLLK
  LWKHECKRVIADRFTVSSDVTWFDKALVSLVEEEFGEEKKLLVDCGIDTYFVDFLRDAPE
  AAGETSEEADAETPKIYEPIESFSHLKERLNMFLQLYNESIRGAGMDMVFFADAMVHLVK
  ISRVIRTPQGNALLVGVGGSGKQSLTRLASFIAGYVSFQITLTRSYNTSNLMEDLKVLYR
  TAGQQGKGITFIFTDNEIKDESFLEYMNNVLSSGEVSNLFARDEIDEINSDLASVMKKEF
  PRCLPTNENLHDYFMSRVRQNLHIVLCFSPVGEKFRNRALKFPALISGCTIDWFSRWPKD
  ALVAVSEHFLTSYDIDCSLEIKKEVVQCMGSFQDGVAEKCVDYFQRFRRSTHVTPKSYLS
  FIQGYKFIYGEKHVEVRTLANRMNTGLEKLKEASESVAALSKELEAKEKELQVANDKADM
  VLKEVTMKAQAAEKVKAEVQKVKDRAQAIVDSISKDKAIAEEKLEAAKPALEEAEAALQT
  IRPSDIATVRTLGRPPHLIMRIMDCVLLLFQRKVSAVKIDLEKSCTMPSWQESLKLMTAG
  NFLQNLQQFPKDTINEEVIEFLSPYFEMPDYNIETAKRVCGNVAGLCSWTKAMASFFSIN
  KEVLPLKANLVVQENRHLLAMQDLQKAQAELDDKQAELDVVQAEYEQAMTEKQTLLEDAE
  RCRHKMQTASTLISGLAGEKERWTEQSQEFAAQTKRLVGDVLLATAFLSYSGPFNQEFRD
  LLLNDWRKEMKARKIPFGKNLNLSEMLIDAPTISEWNLQGLPNDDLSIQNGIIVTKASRY
  PLLIDPQTQGKIWIKNKESRNELQITSLNHKYFRNHLEDSLSLGRPLLIEDVGEELDPAL
  DNVLERNFIKTGSTFKVKVGDKEVDVLDGFRLYITTKLPNPAYTPEISARTSIIDFTVTM
  KGLEDQLLGRVILTEKQELEKERTHLMEDVTANKRRMKELEDNLLYRLTSTQGSLVEDES
  LIVVLSNTKRTAEEVTQKLEISAETEVQINSAREEYRPVATRGSILYFLITEMRLVNEMY
  QTSLRQFLGLFDLSLARSVKSPITSKRIANIIEHMTYEVYKYAARGLYEEHKFLFTLLLT
  LKIDIQRNRVKHEEFLTLIKGGASLDLKACPPKPSKWILDITWLNLVELSKLRQFSDVLD
  QISRNEKMWKIWFDKENPEEEPLPNAYDKSLDCFRRLLLIRSWCPDRTIAQARKYIVDSM
  GEKYAEGVILDLEKTWEESDPRTPLICLLSMGSDPTDSIIALGKRLKIETRYVSMGQGQE
  VHARKLLQQTMANGGWALLQNCHLGLDFMDELMDIIIETELVHDAFRLWMTTEAHKQFPI
  TLLQMSIKFANDPPQGLRAGLKRTYSGVSQDLLDVSSGSQWKPMLYAVAFLHSTVQERRK
  FGALGWNIPYEFNQADFNATVQFIQNHLDDMDVKKGVSWTTIRYMIGEIQYGGRVTDDYD
  KRLLNTFAKVWFSENMFGPDFSFYQGYNIPKCSTVDNYLQYIQSLPAYDSPEVFGLHPNA
  DITYQSKLAKDVLDTILGIQPKDTSGGGDETREAVVARLADDMLEKLPPDYVPFEVKERL
  QKMGPFQPMNIFLRQEIDRMQRVLSLVRSTLTELKLAIDGTIIMSENLRDALDCMFDARI
  PAWWKKASWISSTLGFWFTELIERNSQFTSWVFNGRPHCFWMTGFFNPQGFLTAMRQEIT
  RANKGWALDNMVLCNEVTKWMKDDISAPPTEGVYVYGLYLEGAGWDKRNMKLIESKPKVL
  FELMPVIRIYAENNTLRDPRFYSCPIYKKPVRTDLNYIAAVDLRTAQTPEHWVLRGVALL
  CDVK
• Function: Force generating protein of respiratory cilia. Produces force towards the minus ends of microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Required for structural and functional integrity of the cilia of ependymal cells lining the brain ventricles.
• Tissue Specificity: Expressed in airway epithelial cells (at protein level). Not detected in spermatozoa (at protein level).
• KEGG Pathway:
  Motor proteins (hsa04814)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Pathways of neurodegeneration - multiple diseases (hsa05022)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nasal polyp	DISLP3XE	Definitive	Biomarker	[1]
Primary ciliary dyskinesia 3	DISRGE30	Definitive	Autosomal recessive	[2]
Scleroderma	DISVQ342	Definitive	Biomarker	[3]
Systemic sclerosis	DISF44L6	Definitive	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Bronchiectasis	DIS5MYEE	Strong	Biomarker	[5]
Craniosynostosis	DIS6J405	Strong	Genetic Variation	[6]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[7]
Fleck corneal dystrophy	DISERQJ1	Strong	Biomarker	[8]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[9]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[10]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[11]
Male infertility	DISY3YZZ	Strong	Biomarker	[12]
Otitis media	DISGZDUO	Strong	Biomarker	[13]
Pancreatic cancer	DISJC981	Strong	Biomarker	[14]
Primary ciliary dyskinesia 1	DISPGX6H	Strong	CausalMutation	[15]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[16]
Situs inversus	DISFA7AJ	Strong	Genetic Variation	[17]
Tetralogy of fallot	DISMHFNW	Strong	Biomarker	[18]
Urinary tract infection	DISMT6UV	Strong	Biomarker	[19]
Asthma	DISW9QNS	moderate	Biomarker	[20]
Castration-resistant prostate carcinoma	DISVGAE6	moderate	Biomarker	[21]
Primary ciliary dyskinesia	DISOBC7V	Supportive	Autosomal dominant	[22]
Neoplasm	DISZKGEW	Disputed	Biomarker	[23]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Genetic Variation	[24]
Venous thromboembolism	DISUR7CR	Limited	Biomarker	[25]

5 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 Dynein axonemal heavy chain 5 (DNAH5).	[26]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dynein axonemal heavy chain 5 (DNAH5).	[27]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dynein axonemal heavy chain 5 (DNAH5).	[28]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Dynein axonemal heavy chain 5 (DNAH5).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dynein axonemal heavy chain 5 (DNAH5).	[30]

References

• [1] Absence or mislocalization of DNAH5 is a characteristic marker for motile ciliary abnormality in nasal polyps.Laryngoscope. 2018 Mar;128(3):E97-E104. doi: 10.1002/lary.26983. Epub 2017 Nov 17.
• [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] Chromosome changes in lymphocytes of patients with scleroderma.Ann Genet. 1995;38(3):145-50.
• [4] Predictors of post-cancer diagnosis resignation among Japanese cancer survivors.J Cancer Surviv. 2020 Apr;14(2):106-113. doi: 10.1007/s11764-019-00827-0. Epub 2019 Nov 13.
• [5] Predicting factors for chronic colonization of Pseudomonas aeruginosa in bronchiectasis.Eur J Clin Microbiol Infect Dis. 2019 Dec;38(12):2299-2304. doi: 10.1007/s10096-019-03675-z. Epub 2019 Aug 31.
• [6] A novel mutation of DNAH5 in chronic rhinosinusitis and primary ciliary dyskinesia in a Chinese family.Eur Arch Otorhinolaryngol. 2014 Jun;271(6):1589-94. doi: 10.1007/s00405-013-2788-2. Epub 2013 Oct 23.
• [7] Ciliated conical epithelial cell protrusions point towards a diagnosis of primary ciliary dyskinesia.Respir Res. 2018 Jun 25;19(1):125. doi: 10.1186/s12931-018-0782-3.
• [8] Age-Dependent Subchondral Bone Remodeling and Cartilage Repair in a Minipig Defect Model.Tissue Eng Part C Methods. 2017 Nov;23(11):745-753. doi: 10.1089/ten.TEC.2017.0109. Epub 2017 Oct 27.
• [9] Cilia-related diseases.J Pathol. 2004 Nov;204(4):470-7. doi: 10.1002/path.1652.
• [10] Resources used in the treatment of perianal Crohn's disease and the results in a real-life cohort.Gastroenterol Hepatol. 2018 Jun-Jul;41(6):353-361. doi: 10.1016/j.gastrohep.2018.04.006. Epub 2018 May 11.
• [11] Identification of TRA2B-DNAH5 fusion as a novel oncogenic driver in human lung squamous cell carcinoma.Cell Res. 2016 Oct;26(10):1149-1164. doi: 10.1038/cr.2016.111. Epub 2016 Sep 27.
• [12] Sperm defects in primary ciliary dyskinesia and related causes of male infertility.Cell Mol Life Sci. 2020 Jun;77(11):2029-2048. doi: 10.1007/s00018-019-03389-7. Epub 2019 Nov 28.
• [13] Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus.Hum Mol Genet. 2002 Mar 15;11(6):715-21. doi: 10.1093/hmg/11.6.715.
• [14] Pancreatic Cancer Database: an integrative resource for pancreatic cancer.Cancer Biol Ther. 2014 Aug;15(8):963-7. doi: 10.4161/cbt.29188. Epub 2014 May 19.
• [15] Primary ciliary dyskinesia-causing mutations in Amish and Mennonite communities.J Pediatr. 2013 Aug;163(2):383-7. doi: 10.1016/j.jpeds.2013.01.061. Epub 2013 Mar 7.
• [16] High Norwegian prostate cancer mortality: evidence of over-reporting.Scand J Urol. 2018 Apr;52(2):122-128. doi: 10.1080/21681805.2017.1421260. Epub 2018 Jan 11.
• [17] A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders.Genet Med. 2016 Nov;18(11):1090-1096. doi: 10.1038/gim.2016.1. Epub 2016 Mar 3.
• [18] Heterotaxy and complex structural heart defects in a mutant mouse model of primary ciliary dyskinesia.J Clin Invest. 2007 Dec;117(12):3742-52. doi: 10.1172/JCI33284.
• [19] Is there a conflict between general practitioners applying guidelines for antibiotic prescribing and including their patients' preferences?.Patient Prefer Adherence. 2017 Dec 21;12:9-19. doi: 10.2147/PPA.S147616. eCollection 2018.
• [20] Ventilation Inhomogeneity and Bronchial Basement Membrane Changes in Chronic Neutrophilic Airway Inflammation.Chest. 2020 Apr;157(4):779-789. doi: 10.1016/j.chest.2019.10.023. Epub 2019 Nov 9.
• [21] Rare sugar D-allose induces programmed cell death in hormone refractory prostate cancer cells.Apoptosis. 2008 Sep;13(9):1121-34. doi: 10.1007/s10495-008-0232-7.
• [22] Primary Ciliary Dyskinesia. 2007 Jan 24 [updated 2019 Dec 5]. 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.
• [23] Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration.Acta Neuropathol. 2018 Apr;135(4):569-579. doi: 10.1007/s00401-017-1802-y. Epub 2018 Jan 3.
• [24] A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.BMC Genet. 2015 Dec 3;16:138. doi: 10.1186/s12863-015-0299-4.
• [25] Clinical and laboratory characteristics of children with venous thromboembolism and protein C-deficiency: an observational Israeli-German cohort study.Br J Haematol. 2014 Nov;167(3):385-93. doi: 10.1111/bjh.13039. Epub 2014 Jul 18.
• [26] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [27] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [28] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [29] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [30] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.