Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHGA93D)

• DOT Name: Dynein axonemal light chain 4 (DNAL4)
• Gene Name: DNAL4
• Related Disease:
  Familial congenital mirror movements
  Mirror movements 3
• UniProt ID: DNAL4_HUMAN
• Pfam ID: PF01221
• Sequence:
  MGETEGKKDEADYKRLQTFPLVRHSDMPEEMRVETMELCVTACEKFSNNNESAAKMIKET
  MDKKFGSSWHVVIGEGFGFEITHEVKNLLYLYFGGTLAVCVWKCS
• Function: Force generating protein of respiratory cilia. Produces force towards the minus ends of microtubules. Dynein has ATPase activity.
• KEGG Pathway:
  Motor proteins (hsa04814)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway: Retrograde neurotrophin signalling (R-HSA-177504)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial congenital mirror movements	DISJLV92	Supportive	Autosomal dominant	[1]
Mirror movements 3	DISIODI8	Limited	Unknown	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dynein axonemal light chain 4 (DNAL4).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dynein axonemal light chain 4 (DNAL4).	[4]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Dynein axonemal light chain 4 (DNAL4).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Dynein axonemal light chain 4 (DNAL4).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Dynein axonemal light chain 4 (DNAL4).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Dynein axonemal light chain 4 (DNAL4).	[8]

References

• [1] Identification of a homozygous splice site mutation in the dynein axonemal light chain 4 gene on 22q13.1 in a large consanguineous family from Pakistan with congenital mirror movement disorder. Hum Genet. 2014 Nov;133(11):1419-29. doi: 10.1007/s00439-014-1475-8. Epub 2014 Aug 7.
• [2] The "primary" antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore). 1989 Nov;68(6):366-74.
• [3] 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.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [6] 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.
• [7] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.