Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZGXQ8A)

• DOT Name: Sacsin (SACS)
• Synonyms: DnaJ homolog subfamily C member 29; DNAJC29
• Gene Name: SACS
• Related Disease:
  Beta thalassemia
  Charlevoix-Saguenay spastic ataxia
  Cystic fibrosis
  Familial hypercholesterolemia
  Familial lipoprotein lipase deficiency
  Hypercholesterolemia, familial, 1
  Oculopharyngeal muscular dystrophy
  Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
  Tyrosinemia
  Vitamin D deficiency
  Action myoclonus-renal failure syndrome
  Brachydactyly
  Charcot marie tooth disease
  Congenital nervous system disorder
  Dentatorubral-pallidoluysian atrophy
  Hereditary ataxia
  Hereditary motor and sensory neuropathy
  Multiple sclerosis
  Peripheral neuropathy
  Polyneuropathy
  Progressive myoclonus epilepsy
  Sleep apnea syndrome
  Spastic ataxia
  Trichorhinophalangeal syndrome
  Unverricht-Lundborg syndrome
  Spinocerebellar ataxia type 31
  Cerebellar ataxia
  Intellectual disability
  Movement disorder
  Nervous system disease
• UniProt ID: SACS_HUMAN
• PDB ID: 1IUR; 3O10; 5V44; 5V45; 5V46; 5VSX; 5VSZ
• Pfam ID: PF05168 ; PF00240
• Sequence:
  METKENRWVPVTVLPGCVGCRTVAALASWTVRDVKERIFAETGFPVSEQRLWRGGRELSD
  WIKIGDLTSKNCHLFVNLQSKGLKGGGRFGQTTPPLVDFLKDILRRYPEGGQILKELIQN
  AEDAGATEVKFLYDETQYGTETLWSKDMAPYQGPALYVYNNAVFTPEDWHGIQEIARSRK
  KDDPLKVGRFGIGFNSVYHITDVPCIFSGDQIGMLDPHQTLFGPHESGQCWNLKDDSKEI
  SELSDQFAPFVGIFGSTKETFINGNFPGTFFRFPLRLQPSQLSSNLYNKQKVLELFESFR
  ADADTVLLFLKSVQDVSLYVREADGTEKLVFRVTSSESKALKHERPNSIKILGTAISNYC
  KKTPSNNITCVTYHVNIVLEEESTKDAQKTSWLVCNSVGGRGISSKLDSLADELKFVPII
  GIAMPLSSRDDEAKGATSDFSGKAFCFLPLPPGEESSTGLPVHISGFFGLTDNRRSIKWR
  ELDQWRDPAALWNEFLVMNVVPKAYATLILDSIKRLEMEKSSDFPLSVDVIYKLWPEASK
  VKVHWQPVLEPLFSELLQNAVIYSISCDWVRLEQVYFSELDENLEYTKTVLNYLQSSGKQ
  IAKVPGNVDAAVQLTAASGTTPVRKVTPAWVRQVLRKCAHLGCAEEKLHLLEFVLSDQAY
  SELLGLELLPLQNGNFVPFSSSVSDQDVIYITSAEYPRSLFPSLEGRFILDNLKPHLVAA
  LKEAAQTRGRPCTQLQLLNPERFARLIKEVMNTFWPGRELIVQWYPFDENRNHPSVSWLK
  MVWKNLYIHFSEDLTLFDEMPLIPRTILEEGQTCVELIRLRIPSLVILDDESEAQLPEFL
  ADIVQKLGGFVLKKLDASIQHPLIKKYIHSPLPSAVLQIMEKMPLQKLCNQITSLLPTHK
  DALRKFLASLTDSSEKEKRIIQELAIFKRINHSSDQGISSYTKLKGCKVLHHTAKLPADL
  RLSISVIDSSDEATIRLANMLKIEQLKTTSCLKLVLKDIENAFYSHEEVTQLMLWVLENL
  SSLKNENPNVLEWLTPLKFIQISQEQMVSAGELFDPDIEVLKDLFCNEEGTYFPPSVFTS
  PDILHSLRQIGLKNEASLKEKDVVQVAKKIEALQVGACPDQDVLLKKAKTLLLVLNKNHT
  LLQSSEGKMTLKKIKWVPACKERPPNYPGSLVWKGDLCNLCAPPDMCDVGHAILIGSSLP
  LVESIHVNLEKALGIFTKPSLSAVLKHFKIVVDWYSSKTFSDEDYYQFQHILLEIYGFMH
  DHLNEGKDSFRALKFPWVWTGKKFCPLAQAVIKPIHDLDLQPYLHNVPKTMAKFHQLFKV
  CGSIEELTSDHISMVIQKIYLKSDQDLSEQESKQNLHLMLNIIRWLYSNQIPASPNTPVP
  IHHSKNPSKLIMKPIHECCYCDIKVDDLNDLLEDSVEPIILVHEDIPMKTAEWLKVPCLS
  TRLINPENMGFEQSGQREPLTVRIKNILEEYPSVSDIFKELLQNADDANATECSFLIDMR
  RNMDIRENLLDPGMAACHGPALWSFNNSQFSDSDFVNITRLGESLKRGEVDKVGKFGLGF
  NSVYHITDIPIIMSREFMIMFDPNINHISKHIKDKSNPGIKINWSKQQKRLRKFPNQFKP
  FIDVFGCQLPLTVEAPYSYNGTLFRLSFRTQQEAKVSEVSSTCYNTADIYSLVDEFSLCG
  HRLIIFTQSVKSMYLKYLKIEETNPSLAQDTVIIKKKSCSSKALNTPVLSVLKEAAKLMK
  TCSSSNKKLPSDEPKSSCILQITVEEFHHVFRRIADLQSPLFRGPDDDPAALFEMAKSGQ
  SKKPSDELSQKTVECTTWLLCTCMDTGEALKFSLSESGRRLGLVPCGAVGVQLSEIQDQK
  WTVKPHIGEVFCYLPLRIKTGLPVHINGCFAVTSNRKEIWKTDTKGRWNTTFMRHVIVKA
  YLQVLSVLRDLATSGELMDYTYYAVWPDPDLVHDDFSVICQGFYEDIAHGKGKELTKVFS
  DGSTWVSMKNVRFLDDSILKRRDVGSAAFKIFLKYLKKTGSKNLCAVELPSSVKLGFEEA
  GCKQILLENTFSEKQFFSEVFFPNIQEIEAELRDPLMIFVLNEKVDEFSGVLRVTPCIPC
  SLEGHPLVLPSRLIHPEGRVAKLFDIKDGRFPYGSTQDYLNPIILIKLVQLGMAKDDILW
  DDMLERAVSVAEINKSDHVAACLRSSILLSLIDEKLKIRDPRAKDFAAKYQTIRFLPFLT
  KPAGFSLDWKGNSFKPETMFAATDLYTAEHQDIVCLLQPILNENSHSFRGCGSVSLAVKE
  FLGLLKKPTVDLVINQLKEVAKSVDDGITLYQENITNACYKYLHEALMQNEITKMSIIDK
  LKPFSFILVENAYVDSEKVSFHLNFEAAPYLYQLPNKYKNNFRELFETVGVRQSCTVEDF
  ALVLESIDQERGTKQITEENFQLCRRIISEGIWSLIREKKQEFCEKNYGKILLPDTNLML
  LPAKSLCYNDCPWIKVKDTTVKYCHADIPREVAVKLGAVPKRHKALERYASNVCFTTLGT
  EFGQKEKLTSRIKSILNAYPSEKEMLKELLQNADDAKATEICFVFDPRQHPVDRIFDDKW
  APLQGPALCVYNNQPFTEDDVRGIQNLGKGTKEGNPYKTGQYGIGFNSVYHITDCPSFIS
  GNDILCIFDPHARYAPGATSISPGRMFRDLDADFRTQFSDVLDLYLGTHFKLDNCTMFRF
  PLRNAEMAKVSEISSVPASDRMVQNLLDKLRSDGAELLMFLNHMEKISICEIDKSTGALN
  VLYSVKGKITDGDRLKRKQFHASVIDSVTKKRQLKDIPVQQITYTMDTEDSEGNLTTWLI
  CNRSGFSSMEKVSKSVISAHKNQDITLFPRGGVAACITHNYKKPHRAFCFLPLSLETGLP
  FHVNGHFALDSARRNLWRDDNGVGVRSDWNNSLMTALIAPAYVELLIQLKKRYFPGSDPT
  LSVLQNTPIHVVKDTLKKFLSFFPVNRLDLQPDLYCLVKALYNCIHEDMKRLLPVVRAPN
  IDGSDLHSAVIITWINMSTSNKTRPFFDNLLQDELQHLKNADYNITTRKTVAENVYRLKH
  LLLEIGFNLVYNCDETANLYHCLIDADIPVSYVTPADIRSFLMTFSSPDTNCHIGKLPCR
  LQQTNLKLFHSLKLLVDYCFKDAEENEIEVEGLPLLITLDSVLQTFDAKRPKFLTTYHEL
  IPSRKDLFMNTLYLKYSNILLNCKVAKVFDISSFADLLSSVLPREYKTKSCTKWKDNFAS
  ESWLKNAWHFISESVSVKEDQEETKPTFDIVVDTLKDWALLPGTKFTVSANQLVVPEGDV
  LLPLSLMHIAVFPNAQSDKVFHALMKAGCIQLALNKICSKDSAFVPLLSCHTANIESPTS
  ILKALHYMVQTSTFRAEKLVENDFEALLMYFNCNLNHLMSQDDIKILKSLPCYKSISGRY
  VSIGKFGTCYVLTKSIPSAEVEKWTQSSSSAFLEEKIHLKELYEVIGCVPVDDLEVYLKH
  LLPKIENLSYDAKLEHLIYLKNRLSSAEELSEIKEQLFEKLESLLIIHDANSRLKQAKHF
  YDRTVRVFEVMLPEKLFIPNDFFKKLEQLIKPKNHVTFMTSWVEFLRNIGLKYILSQQQL
  LQFAKEISVRANTENWSKETLQNTVDILLHHIFQERMDLLSGNFLKELSLIPFLCPERAP
  AEFIRFHPQYQEVNGTLPLIKFNGAQVNPKFKQCDVLQLLWTSCPILPEKATPLSIKEQE
  GSDLGPQEQLEQVLNMLNVNLDPPLDKVINNCRNICNITTLDEEMVKTRAKVLRSIYEFL
  SAEKREFRFQLRGVAFVMVEDGWKLLKPEEVVINLEYESDFKPYLYKLPLELGTFHQLFK
  HLGTEDIISTKQYVEVLSRIFKNSEGKQLDPNEMRTVKRVVSGLFRSLQNDSVKVRSDLE
  NVRDLALYLPSQDGRLVKSSILVFDDAPHYKSRIQGNIGVQMLVDLSQCYLGKDHGFHTK
  LIMLFPQKLRPRLLSSILEEQLDEETPKVCQFGALCSLQGRLQLLLSSEQFITGLIRIMK
  HENDNAFLANEEKAIRLCKALREGLKVSCFEKLQTTLRVKGFNPIPHSRSETFAFLKRFG
  NAVILLYIQHSDSKDINFLLALAMTLKSATDNLISDTSYLIAMLGCNDIYRIGEKLDSLG
  VKYDSSEPSKLELPMPGTPIPAEIHYTLLMDPMNVFYPGEYVGYLVDAEGGDIYGSYQPT
  YTYAIIVQEVEREDADNSSFLGKIYQIDIGYSEYKIVSSLDLYKFSRPEESSQSRDSAPS
  TPTSPTEFLTPGLRSIPPLFSGRESHKTSSKHQSPKKLKVNSLPEILKEVTSVVEQAWKL
  PESERKKIIRRLYLKWHPDKNPENHDIANEVFKHLQNEINRLEKQAFLDQNADRASRRTF
  STSASRFQSDKYSFQRFYTSWNQEATSHKSERQQQNKEKCPPSAGQTYSQRFFVPPTFKS
  VGNPVEARRWLRQARANFSAARNDLHKNANEWVCFKCYLSTKLALIAADYAVRGKSDKDV
  KPTALAQKIEEYSQQLEGLTNDVHTLEAYGVDSLKTRYPDLLPFPQIPNDRFTSEVAMRV
  MECTACIIIKLENFMQQKV
• Function: Co-chaperone which acts as a regulator of the Hsp70 chaperone machinery and may be involved in the processing of other ataxia-linked proteins.
• Tissue Specificity: Highly expressed in the central nervous system. Also found in skeletal muscle and at low levels in pancreas.

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Beta thalassemia	DIS5RCQK	Definitive	Altered Expression	[1]
Charlevoix-Saguenay spastic ataxia	DISE8X81	Definitive	Autosomal recessive	[2]
Cystic fibrosis	DIS2OK1Q	Definitive	Altered Expression	[1]
Familial hypercholesterolemia	DISC06IX	Definitive	Altered Expression	[1]
Familial lipoprotein lipase deficiency	DIS0M7NJ	Definitive	Altered Expression	[1]
Hypercholesterolemia, familial, 1	DISU411W	Definitive	Altered Expression	[1]
Oculopharyngeal muscular dystrophy	DISF4G07	Definitive	Altered Expression	[1]
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	DIS84UUI	Definitive	Genetic Variation	[3]
Tyrosinemia	DISI8Q9Q	Definitive	Altered Expression	[1]
Vitamin D deficiency	DISAWKYI	Definitive	Altered Expression	[1]
Action myoclonus-renal failure syndrome	DISI2BZN	Strong	Biomarker	[4]
Brachydactyly	DIS2533F	Strong	Genetic Variation	[5]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[6]
Congenital nervous system disorder	DIS2BIP8	Strong	Biomarker	[7]
Dentatorubral-pallidoluysian atrophy	DISHWE0K	Strong	Biomarker	[4]
Hereditary ataxia	DIS6JNI3	Strong	Genetic Variation	[8]
Hereditary motor and sensory neuropathy	DISR0X2K	Strong	Genetic Variation	[9]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[10]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[9]
Polyneuropathy	DISB9G3W	Strong	Biomarker	[11]
Progressive myoclonus epilepsy	DISAMCNS	Strong	Biomarker	[4]
Sleep apnea syndrome	DISER6KS	Strong	Biomarker	[12]
Spastic ataxia	DISIRRA9	Strong	Biomarker	[13]
Trichorhinophalangeal syndrome	DISO1AEK	Strong	Genetic Variation	[5]
Unverricht-Lundborg syndrome	DISG4WLX	Strong	Genetic Variation	[4]
Spinocerebellar ataxia type 31	DISUPR8L	Disputed	Genetic Variation	[14]
Cerebellar ataxia	DIS9IRAV	Limited	Biomarker	[11]
Intellectual disability	DISMBNXP	Limited	Biomarker	[15]
Movement disorder	DISOJJ2D	Limited	CausalMutation	[15]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Sacsin (SACS).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Sacsin (SACS).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sacsin (SACS).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sacsin (SACS).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sacsin (SACS).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sacsin (SACS).	[18]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sacsin (SACS).	[22]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Sacsin (SACS).	[23]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Sacsin (SACS).	[24]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Sacsin (SACS).	[25]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Sacsin (SACS).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Sacsin (SACS).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Sacsin (SACS).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sacsin (SACS).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Sacsin (SACS).	[27]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Sacsin (SACS).	[27]

References

• [1] Human genetics: lessons from Quebec populations.Annu Rev Genomics Hum Genet. 2001;2:69-101. doi: 10.1146/annurev.genom.2.1.69.
• [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] Molecular diagnosis of known recessive ataxias by homozygosity mapping with SNP arrays.J Neurol. 2011 Jan;258(1):56-67. doi: 10.1007/s00415-010-5682-5. Epub 2010 Aug 27.
• [4] A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet. 2015 Jan;47(1):39-46. doi: 10.1038/ng.3144. Epub 2014 Nov 17.
• [5] Syndrome disintegration: Exome sequencing reveals that Fitzsimmons syndrome is a co-occurrence of multiple events.Am J Med Genet A. 2016 Jul;170(7):1820-5. doi: 10.1002/ajmg.a.37684. Epub 2016 May 2.
• [6] Early-onset axonal Charcot-Marie-Tooth disease due to SACS mutation.Neuromuscul Disord. 2018 Feb;28(2):169-172. doi: 10.1016/j.nmd.2017.11.008. Epub 2017 Nov 24.
• [7] Assessment of whole-brain white matter by DTI in autosomal recessive spastic ataxia of Charlevoix-Saguenay.AJNR Am J Neuroradiol. 2013 Oct;34(10):1952-7. doi: 10.3174/ajnr.A3488. Epub 2013 Apr 18.
• [8] Novel mutations in the sacsin gene in ataxia patients from Maritime Canada.J Neurol Sci. 2010 Jan 15;288(1-2):79-87. doi: 10.1016/j.jns.2009.09.034. Epub 2009 Nov 4.
• [9] SACS variants are a relevant cause of autosomal recessive hereditary motor and sensory neuropathy.Hum Genet. 2018 Dec;137(11-12):911-919. doi: 10.1007/s00439-018-1952-6. Epub 2018 Nov 21.
• [10] Copy number variation in pediatric multiple sclerosis.Mult Scler. 2013 Jul;19(8):1014-21. doi: 10.1177/1352458512469696. Epub 2012 Dec 13.
• [11] A novel homozygous SACS mutation identified by whole exome sequencing-genotype phenotype correlations of all published cases.J Mol Neurosci. 2020 Jan;70(1):131-141. doi: 10.1007/s12031-019-01410-z. Epub 2019 Nov 7.
• [12] Nutrigenetic genotyping study in relation to Sleep Apnea Clinical Score.Sleep Breath. 2019 Jun;23(2):659-663. doi: 10.1007/s11325-018-1742-3. Epub 2018 Oct 17.
• [13] Sacsin, mutated in the ataxia ARSACS, regulates intermediate filament assembly and dynamics.FASEB J. 2019 Feb;33(2):2982-2994. doi: 10.1096/fj.201801556R. Epub 2018 Oct 17.
• [14] Mutations in rare ataxia genes are uncommon causes of sporadic cerebellar ataxia.Mov Disord. 2012 Mar;27(3):442-6. doi: 10.1002/mds.24064. Epub 2012 Jan 27.
• [15] Novel SACS mutations associated with intellectual disability, epilepsy and widespread supratentorial abnormalities.J Neurol Sci. 2016 Dec 15;371:105-111. doi: 10.1016/j.jns.2016.10.032. Epub 2016 Oct 21.
• [16] Novel homozygous variants in ATCAY, MCOLN1, and SACS in complex neurological disorders.Parkinsonism Relat Disord. 2018 Jun;51:91-95. doi: 10.1016/j.parkreldis.2018.02.005. Epub 2018 Feb 6.
• [17] 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.
• [18] 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.
• [19] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [20] 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.
• [21] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [22] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [23] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [24] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [25] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [26] 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.
• [27] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [28] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.