Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6DXD3Q)

• DOT Name: Ankyrin repeat and SAM domain-containing protein 6 (ANKS6)
• Synonyms: Ankyrin repeat domain-containing protein 14; SamCystin; Sterile alpha motif domain-containing protein 6; SAM domain-containing protein 6
• Gene Name: ANKS6
• Related Disease:
  Nephronophthisis 16
  Autosomal dominant polycystic kidney disease
  Cystic kidney disease
  Liver cirrhosis
  Nephronophthisis
  Normal pressure hydrocephalus
  Polycystic kidney disease 2
  Polycystic liver disease 1
  Nephronophthisis 1
  Nephronophthisis 2
  Episodic kinesigenic dyskinesia 1
  Polycystic kidney disease
• UniProt ID: ANKS6_HUMAN
• PDB ID: 4NL9
• Pfam ID: PF00023 ; PF12796 ; PF00536
• Sequence:
  MGEGGLPPAFQLLLRACDQGDTETARRLLEPGAAEPAERGAEPEAGAEPAGAEVAGPGAA
  AAGAVGAPVPVDCSDEAGNTALQFAAAGGHEPLVRFLLRRGASVNSRNHYGWSALMQAAR
  FGHVSVAHLLLDHGADVNAQNRLGASVLTVASRGGHLGVVKLLLEAGAFVDHHHPSGEQL
  GLGGSRDEPLDITALMAAIQHGHEAVVRLLMEWGADPNHAARTVGWSPLMLAALTGRLGV
  AQQLVEKGANPDHLSVLEKTAFEVALDCKHRDLVDYLDPLTTVRPKTDEEKRRPDIFHAL
  KMGNFQLVKEIADEDPSHVNLVNGDGATPLMLAAVTGQLALVQLLVERHADVDKQDSVHG
  WTALMQATYHGNKEIVKYLLNQGADVTLRAKNGYTAFDLVMLLNDPDTELVRLLASVCMQ
  VNKDKGRPSHQPPLPHSKVRQPWSIPVLPDDKGGLKSWWNRMSNRFRKLKLMQTLPRGLS
  SNQPLPFSDEPEPALDSTMRAAPQDKTSRSALPDAAPVTKDNGPGSTRGEKEDTLLTTML
  RNGAPLTRLPSDKLKAVIPPFLPPSSFELWSSDRSRTRHNGKADPMKTALPQRASRGHPV
  GGGGTDTTPVRPVKFPSLPRSPASSANSGNFNHSPHSSGGSSGVGVSRHGGELLNRSGGS
  IDNVLSQIAAQRKKAAGLLEQKPSHRSSPVGPAPGSSPSELPASPAGGSAPVGKKLETSK
  RPPSGTSTTSKSTSPTLTPSPSPKGHTAESSVSSSSSHRQSKSSGGSSSGTITDEDELTG
  ILKKLSLEKYQPIFEEQEVDMEAFLTLTDGDLKELGIKTDGSRQQILAAISELNAGKGRE
  RQILQETIHNFHSSFESSASNTRAPGNSPCA
• Function: Required for renal function.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephronophthisis 16	DISE0CCK	Definitive	Autosomal recessive	[1]
Autosomal dominant polycystic kidney disease	DISBHWUI	Strong	Biomarker	[2]
Cystic kidney disease	DISRT1LM	Strong	Biomarker	[3]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[4]
Nephronophthisis	DISXU4HY	Strong	Genetic Variation	[5]
Normal pressure hydrocephalus	DISOEFO9	Strong	Biomarker	[6]
Polycystic kidney disease 2	DIS4UQIF	Strong	Biomarker	[2]
Polycystic liver disease 1	DIS52T2A	Strong	Biomarker	[2]
Nephronophthisis 1	DIS7QNQ3	Supportive	Autosomal recessive	[4]
Nephronophthisis 2	DIS5Y5KV	Supportive	Autosomal recessive	[4]
Episodic kinesigenic dyskinesia 1	DISGVQMP	Limited	Genetic Variation	[7]
Polycystic kidney disease	DISWS3UY	Limited	Biomarker	[3]

1 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 Ankyrin repeat and SAM domain-containing protein 6 (ANKS6).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ankyrin repeat and SAM domain-containing protein 6 (ANKS6).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ankyrin repeat and SAM domain-containing protein 6 (ANKS6).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ankyrin repeat and SAM domain-containing protein 6 (ANKS6).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ankyrin repeat and SAM domain-containing protein 6 (ANKS6).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Ankyrin repeat and SAM domain-containing protein 6 (ANKS6).	[13]

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] Altered expression pattern of polycystin-2 in acute and chronic renal tubular diseases.J Am Soc Nephrol. 2002 Jul;13(7):1855-64. doi: 10.1097/01.asn.0000018402.33620.c7.
• [3] The SAM domain of ANKS6 has different interacting partners and mutations can induce different cystic phenotypes.Kidney Int. 2015 Aug;88(2):299-310. doi: 10.1038/ki.2015.122. Epub 2015 Jun 3.
• [4] ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat Genet. 2013 Aug;45(8):951-6. doi: 10.1038/ng.2681. Epub 2013 Jun 23.
• [5] Whole-exome sequencing identifies a novel compound heterozygous mutation of ANKS6 gene in a Chinese nephronophthisis patient.Clin Chim Acta. 2020 Feb;501:131-135. doi: 10.1016/j.cca.2019.10.030. Epub 2019 Oct 31.
• [6] Anks3 alters the sub-cellular localization of the Nek7 kinase.Biochem Biophys Res Commun. 2015 Aug 28;464(3):901-7. doi: 10.1016/j.bbrc.2015.07.063. Epub 2015 Jul 15.
• [7] High-resolution genetic localization of a modifying locus affecting disease severity in the juvenile cystic kidneys (jck) mouse model of polycystic kidney disease.Mamm Genome. 2016 Jun;27(5-6):191-9. doi: 10.1007/s00335-016-9633-z. Epub 2016 Apr 25.
• [8] 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.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.