Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4G6E70)

• DOT Name: Dynein axonemal heavy chain 17 (DNAH17)
• Synonyms: Axonemal beta dynein heavy chain 17; Axonemal dynein heavy chain-like protein 1; Ciliary dynein heavy chain 17; Ciliary dynein heavy chain-like protein 1; Dynein axonemal light chain 2
• Gene Name: DNAH17
• Related Disease:
  Chronic kidney disease
  Chronic renal failure
  Spermatogenic failure 39
  Hepatocellular carcinoma
  Male infertility
  Obsolete non-syndromic male infertility due to sperm motility disorder
  Acute myelogenous leukaemia
• UniProt ID: DYH17_HUMAN
• Pfam ID: PF12774 ; PF12775 ; PF12780 ; PF12781 ; PF17857 ; PF18198 ; PF08385 ; PF08393 ; PF17852 ; PF18199 ; PF03028 ; PF12777
• Sequence:
  MTMAPDVRLEYLEEVASIVLKFKPDKWSKLIGAEENVALFTEFFEKPDVQVLVLTLNAAG
  MIIPCLGFPQSLKSKGVYFIKTKSENINKDNYRARLLYGDISPTPVDQLIAVVEEVLSSL
  LNQSENMAGWPQVVSEDIVKQVHRLKNEMFVMSGKIKGKTLLPIPEHLGSLDGTLESMER
  IPSSLDNLLLHAIETTIIDWSHQIRDVLSKDSAQALLDGLHPLPQVEFEFWDTRLLNLKC
  IHEQLNRPKVNKIVEILEKAKSCYWPALQNVYTNVTEGLKEANDIVLYLKPLRILLEEME
  QADFTMLPTFIAKVLDTICFIWATSEYYNTPARIIVILQEFCNQIIEMTRTFLSPEEVLK
  GLQGEIEEVLSGISLAVNVLKELYQTYDFCCVNMKLFFKDKEPVPWEFPSSLAFSRINSF
  FQRIQTIEELYKTAIEFLKLEKIELGGVRGNLLGSLVTRIYDEVFELVKVFADCKYDPLD
  PGDSNFDRDYADFEIKIQDLDRRLATIFCQGFDDCSCIKSSAKLLYMCGGLMERPLILAE
  VAPRYSVMLELFDAELDNAKILYDAQMAASEEGNIPLIHKNMPPVAGQLKWSLELQERLE
  VSMKHLKHVEHPVMSGAEAKLTYQKYDEMMELLRCHREKIYQQWVAGVDQDCHFNLGQPL
  ILRDAASNLIHVNFSKALVAVLREVKYLNFQQQKEIPDSAESLFSENETFRKFVGNLELI
  VGWYNEIKTIVKAVEFLLIKSELEAIDVKLLSAETTLFWNGEGVFQYIQEVREILHNLQN
  RMQKAKQNIEGISQAMKDWSANPLFERKDNKKEALLDLDGRIANLNKRYAAVRDAGVKIQ
  AMVAENAELFRADTLSLPWKDYVIYIDDMVLDEFDQFIRKSLSFLMDNMVIDESIAPLFE
  IRMELDEDGLTFNPTLEVGSDRGFLALIEGLVNDIYNVARLIPRLAKDRMNYKMDLEDNT
  DLIEMREEVSSLVINAMKEAEEYQDSFERYSYLWTDNLQEFMKNFLIYGCAVTAEDLDTW
  TDDTIPKTPPTLAQFQEQIDSYEKLYEEVSKCENTKVFHGWLQCDCRPFKQALLSTIRRW
  GFMFKRHLSNHVTNSLADLEAFMKVARMGLTKPLKEGDYDGLVEVMGHLMKVKERQAATD
  NMFEPLKQTIELLKTYGEEMPEEIHLKLQELPEHWANTKKLAIQVKLTVAPLQANEVSIL
  RRKCQQFELKQHEFRERFRREAPFSFSDPNPYKSLNKQQKSISAMEGIMEALSKSGGLFE
  VPVPDYKQLKACHREVRLLKELWDMVVVVNTSIEDWKTTKWKDINVEQMDIDCKKFAKDM
  RSLDKEMKTWDAFVGLDNTVKNVITSLRAVSELQNPAIRERHWQQLMQATQVKFKMSEET
  TLADLLQLNLHSYEDEVRNIVDKAVKESGMEKVLKALDSTWSMMEFQHEPHPRTGTMMLK
  SSEVLVETLEDNQVQLQNLMMSKYLAHFLKEVTSWQQKLSTADSVISIWFEVQRTWSHLE
  SIFIGSEDIRTQLPGDSQRFDDINQEFKALMEDAVKTPNVVEATSKPGLYNKLEALKKSL
  AICEKALAEYLETKRLAFPRFYFVSSADLLDILSNGNDPVEVSRHLSKLFDSLCKLKFRL
  DASDKPLKVGLGMYSKEDEYMVFDQECDLSGQVEVWLNRVLDRMCSTLRHEIPEAVVTYE
  EKPREQWILDYPAQVALTCTQIWWTTEVGLAFARLEEGYENAIRDYNKKQISQLNVLITL
  LMGNLNAGDRMKIMTICTIDVHARDVVAKMIVAKVESSQAFTWQAQLRHRWDEEKRHCFA
  NICDAQIQYSYEYLGNTPRLVITPLTDRCYITLTQSLHLIMGGAPAGPAGTGKTETTKDL
  GRALGTMVYVFNCSEQMDYKSCGNIYKGLAQTGAWGCFDEFNRISVEVLSVIAVQVKCVQ
  DAIRAKKKAFNFLGEIIGLIPTVGIFITMNPGYAGRAELPENLKALFRPCAMVVPDFELI
  CEIMLMAEGFLEARLLARKFITLYTLCKELLSKQDHYDWGLRAIKSVLVVAGSLKRGDPS
  RAEDQVLMRALRDFNIPKIVTDDLPVFMGLIGDLFPALDVPRKRDLNFEKIIKQSIVELK
  LQAEDSFVLKVVQLEELLQVRHSVFIVGNAGSGKSQVLKSLNKTYQNLKRKPVAVDLDPK
  AVTCDELFGIINPVTREWKDGLFSTIMRDLANITHDGPKWIILDGDIDPMWIESLNTVMD
  DNKVLTLASNERIPLNRTMRLVFEISHLRTATPATVSRAGILYINPADLGWNPVVSSWIE
  RRKVQSEKANLMILFDKYLPTCLDKLRFGFKKITPVPEITVIQTILYLLECLLTEKTVPP
  DSPRELYELYFVFTCFWAFGGAMFQDQLVDYRVEFSKWWINEFKTIKFPSQGTIFDYYID
  PDTKKFLPWTDKVPSFELDPDVPLQASLVHTTETIRIRYFMDLLMEKSWPVMLVGNAGTG
  KSVLMGDKLESLNTDNYLVQAVPFNFYTTSAMLQGVLEKPLEKKSGRNYGPPGTKKLVYF
  IDDMNMPEVDKYGTVAPHTLIRQHMDHRHWYDRHKLTLKDIHNCQYVACMNPTSGSFTID
  SRLQRHFCVFAVSFPGQEALTTIYNTILTQHLAFRSVSMAIQRISSQLVAAALALHQKIT
  ATFLPTAIKFHYVFNLRDLSNIFQGLLFSTAEVLKTPLDLVRLWLHETERVYGDKMVDEK
  DQETLHRVTMASTKKFFDDLGDELLFAKPNIFCHFAQGIGDPKYVPVTDMAPLNKLLVDV
  LDSYNEVNAVMNLVLFEDAVAHICRINRILESPRGNALLVGVGGSGKQSLSRLAAYISGL
  DVFQITLKKGYGIPDLKIDLAAQYIKAAVKNVPSVFLMTDSQVAEEQFLVLINDLLASGE
  IPGLFMEDEVENIISSMRPQVKSLGMNDTRETCWKFFIEKVRRQLKVILCFSPVGSVLRV
  RARKFPAVVNCTAIDWFHEWPEDALVSVSARFLEETEGIPWEVKASISFFMSYVHTTVNE
  MSRVYLATERRYNYTTPKTFLEQIKLYQNLLAKKRTELVAKIERLENGLMKLQSTASQVD
  DLKAKLAIQEAELKQKNESADQLIQVVGIEAEKVSKEKAIADQEEVKVEVINKNVTEKQK
  ACETDLAKAEPALLAAQEALDTLNKNNLTELKSFGSPPDAVVNVTAAVMILTAPGGKIPK
  DKSWKAAKIMMGKVDTFLDSLKKFDKEHIPEACLKAFKPYQGNPTFDPEFIRSKSTAAAG
  LCSWCINIVRFYEVYCDVAPKRQALEEANAELAEAQEKLSRIKNKIAELNANLSNLTSAF
  EKATAEKIKCQQEADATNRVILLANRLVGGLASENIRWAESVENFRSQGVTLCGDVLLIS
  AFVSYVGYFTKKYRNELMEKFWIPYIHNLKVPIPITNGLDPLSLLTDDADVATWNNQGLP
  SDRMSTENATILGNTERWPLIVDAQLQGIKWIKNKYRSELKAIRLGQKSYLDVIEQAISE
  GDTLLIENIGETVDPVLDPLLGRNTIKKGKYIKIGDKEVEYHPKFRLILHTKYFNPHYKP
  EMQAQCTLINFLVTRDGLEDQLLAAVVAKERPDLEQLKANLTKSQNEFKIVLKELEDSLL
  ARLSAASGNFLGDTALVENLETTKHTASEIEEKVVEAKITEVKINEARENYRPAAERASL
  LYFILNDLNKINPVYQFSLKAFNVVFEKAIQRTTPANEVKQRVINLTDEITYSVYMYTAR
  GLFERDKLIFLAQVTFQVLSMKKELNPVELDFLLRFPFKAGVVSPVDFLQHQGWGGIKAL
  SEMDEFKNLDSDIEGSAKRWKKLVESEAPEKEIFPKEWKNKTALQKLCMVRCLRPDRMTY
  AIKNFVEEKMGSKFVEGRSVEFSKSYEESSPSTSIFFILSPGVDPLKDVEALGKKLGFTI
  DNGKLHNVSLGQGQEVVAENALDVAAEKGHWVILQNIHLVARWLGTLDKKLEHYSTGSHE
  DYRVFISAEPAPSPETHIIPQGILENAIKITNEPPTGMHANLHKALDLFTQDTLEMCTKE
  MEFKCMLFALCYFHAVVAERRKFGAQGWNRSYPFNNGDLTISINVLYNYLEANPKVPWDD
  LRYLFGEIMYGGHITDDWDRRLCRTYLAEYIRTEMLEGDVLLAPGFQIPPNLDYKGYHEY
  IDENLPPESPYLYGLHPNAEIGFLTVTSEKLFRTVLEMQPKETDSGAGTGVSREEKVKAV
  LDDILEKIPETFNMAEIMAKAAEKTPYVVVAFQECERMNILTNEMRRSLKELNLGLKGEL
  TITTDVEDLSTALFYDTVPDTWVARAYPSMMGLAAWYADLLLRIRELEAWTTDFALPTTV
  WLAGFFNPQSFLTAIMQSMARKNEWPLDKMCLSVEVTKKNREDMTAPPREGSYVYGLFME
  GARWDTQTGVIAEARLKELTPAMPVIFIKAIPVDRMETKNIYECPVYKTRIRGPTYVWTF
  NLKTKEKAAKWILAAVALLLQV
• Function: Force generating protein component of the outer dynein arms (ODAs) in the sperm flagellum. 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 (Probable). Plays a major role in sperm motility, implicated in sperm flagellar assembly and beating.
• Tissue Specificity: Expressed in testis . Expressed in spermatozoa (at protein level). Not detected in airway epithelial cells (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

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Definitive	Genetic Variation	[1]
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
Spermatogenic failure 39	DISWTPU4	Definitive	Autosomal recessive	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[4]
Obsolete non-syndromic male infertility due to sperm motility disorder	DISG7641	Supportive	Autosomal recessive	[5]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Dynein axonemal heavy chain 17 (DNAH17).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Dynein axonemal heavy chain 17 (DNAH17).	[11]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Dynein axonemal heavy chain 17 (DNAH17).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dynein axonemal heavy chain 17 (DNAH17).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dynein axonemal heavy chain 17 (DNAH17).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Dynein axonemal heavy chain 17 (DNAH17).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dynein axonemal heavy chain 17 (DNAH17).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dynein axonemal heavy chain 17 (DNAH17).	[13]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Dynein axonemal heavy chain 17 (DNAH17).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Dynein axonemal heavy chain 17 (DNAH17).	[14]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Dynein axonemal heavy chain 17 (DNAH17).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Dynein axonemal heavy chain 17 (DNAH17).	[16]

References

• [1] Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms.J Am Soc Nephrol. 2018 May;29(5):1513-1524. doi: 10.1681/ASN.2017101099. Epub 2018 Mar 15.
• [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] The association between methylation patterns of DNAH17 and clinicopathological factors in hepatocellular carcinoma.Cancer Med. 2019 Jan;8(1):337-350. doi: 10.1002/cam4.1930. Epub 2018 Dec 21.
• [4] A DNAH17 missense variant causes flagella destabilization and asthenozoospermia.J Exp Med. 2020 Feb 3;217(2):e20182365. doi: 10.1084/jem.20182365.
• [5] Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia. Am J Hum Genet. 2019 Jul 3;105(1):198-212. doi: 10.1016/j.ajhg.2019.04.015. Epub 2019 Jun 6.
• [6] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] 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.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [15] 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.
• [16] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.