Details of Drug Off-Target (DOT)

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

• DOT Name: Dynein axonemal assembly factor 1 (DNAAF1)
• Synonyms: Leucine-rich repeat-containing protein 50
• Gene Name: DNAAF1
• Related Disease:
  Primary ciliary dyskinesia 13
  Cardiac failure
  Congestive heart failure
  High blood pressure
  Neoplasm
  Polycystic kidney disease
  Primary ciliary dyskinesia 1
  Seminoma
  Testicular germ cell tumor
  Primary ciliary dyskinesia
• UniProt ID: DAAF1_HUMAN
• Pfam ID: PF14580
• Sequence:
  MHPEPSEPATGGAAELDCAQEPGVEESAGDHGSAGRGGCKEEINDPKEICVGSSDTSYHS
  QQKQSGDNGSGGHFAHPREDREDRGPRMTKSSLQKLCKQHKLYITPALNDTLYLHFKGFD
  RIENLEEYTGLRCLWLQSNGIQKIENLEAQTELRCLFLQMNLLRKIENLEPLQKLDALNL
  SNNYIKTIENLSCLPVLNTLQMAHNHLETVEDIQHLQECLRLCVLDLSHNKLSDPEILSI
  LESMPDLRVLNLMGNPVIRQIPNYRRTVTVRLKHLTYLDDRPVFPKDRACAEAWARGGYA
  AEKEERQQWESRERKKITDSIEALAMIKQRAEERKRQRESQERGEMTSSDDGENVPASAE
  GKEEPPGDRETRQKMELFVKESFEAKDELCPEKPSGEEPPVEAKREDGGPEPEGTLPAET
  LLLSSPVEVKGEDGDGEPEGTLPAEAPPPPPPVEVKGEDGDQEPEGTLPAETLLLSPPVK
  VKGEDGDREPEGTLPAEAPPPPPLGAAREEPTPQAVATEGVFVTELDGTRTEDLETIRLE
  TKETFCIDDLPDLEDDDETGKSLEDQNMCFPKIEVISSLSDDSDPELDYTSLPVLENLPT
  DTLSNIFAVSKDTSKAARVPFTDIFKKEAKRDLEIRKQDTKSPRPLIQELSDEDPSGQLL
  MPPTCQRDAAPLTSSGDRDSDFLAASSPVPTESAATPPETCVGVAQPSQALPTWDLTAFP
  APKAS
• Function: Cilium-specific protein required for the stability of the ciliary architecture. Plays a role in cytoplasmic preassembly of dynein arms. Involved in regulation of microtubule-based cilia and actin-based brush border microvilli.
• Tissue Specificity: Mainly expressed in trachea and testis.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Primary ciliary dyskinesia 13	DISLU7XA	Definitive	Autosomal recessive	[1]
Cardiac failure	DISDC067	Strong	Biomarker	[2]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[2]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Polycystic kidney disease	DISWS3UY	Strong	Biomarker	[5]
Primary ciliary dyskinesia 1	DISPGX6H	Strong	CausalMutation	[6]
Seminoma	DIS3J8LJ	Strong	Biomarker	[4]
Testicular germ cell tumor	DIS5RN24	Strong	Genetic Variation	[7]
Primary ciliary dyskinesia	DISOBC7V	Supportive	Autosomal dominant	[8]

6 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 Dynein axonemal assembly factor 1 (DNAAF1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dynein axonemal assembly factor 1 (DNAAF1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dynein axonemal assembly factor 1 (DNAAF1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dynein axonemal assembly factor 1 (DNAAF1).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Dynein axonemal assembly factor 1 (DNAAF1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Dynein axonemal assembly factor 1 (DNAAF1).	[14]

References

• [1] 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.
• [2] Shock Wave Therapy Improves Cardiac Function in a Model of Chronic Ischemic Heart Failure: Evidence for a Mechanism Involving VEGF Signaling and the Extracellular Matrix.J Am Heart Assoc. 2018 Oct 16;7(20):e010025. doi: 10.1161/JAHA.118.010025.
• [3] Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide.Hypertension. 2017 Jan;69(1):51-59. doi: 10.1161/HYPERTENSIONAHA.116.08267. Epub 2016 Oct 31.
• [4] Mutations in LRRC50 predispose zebrafish and humans to seminomas.PLoS Genet. 2013 Apr;9(4):e1003384. doi: 10.1371/journal.pgen.1003384. Epub 2013 Apr 11.
• [5] LRRC50, a conserved ciliary protein implicated in polycystic kidney disease.J Am Soc Nephrol. 2008 Jun;19(6):1128-38. doi: 10.1681/ASN.2007080917. Epub 2008 Apr 2.
• [6] Deletions and point mutations of LRRC50 cause primary ciliary dyskinesia due to dynein arm defects. Am J Hum Genet. 2009 Dec;85(6):883-9. doi: 10.1016/j.ajhg.2009.10.018.
• [7] Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility.Nat Commun. 2016 Dec 20;7:13840. doi: 10.1038/ncomms13840.
• [8] 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.
• [9] 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.
• [10] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [11] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] 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.
• [14] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.