Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ7LJX4)

• DOT Name: Spatacsin (SPG11)
• Synonyms: Colorectal carcinoma-associated protein; Spastic paraplegia 11 protein
• Gene Name: SPG11
• Related Disease:
  Amyotrophic lateral sclerosis
  Cognitive impairment
  Hereditary spastic paraplegia 11
  Paraplegia
  Amyotrophic lateral sclerosis type 2, juvenile
  Amyotrophic lateral sclerosis type 5
  Cerebellar ataxia
  Cerebrotendinous xanthomatosis
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease axonal type 2X
  Complex hereditary spastic paraplegia
  Dementia
  Epilepsy
  Hereditary spastic paraplegia 4
  Intellectual disability
  Juvenile-onset Parkinson disease
  Mental disorder
  Multiple sclerosis
  Parkinsonian disorder
  Polyneuropathy
  Relapsing-remitting multiple sclerosis
  Tarsal-carpal coalition syndrome
  Vascular purpura
  Axonal neuropathy
  Bipolar disorder
  Hereditary spastic paraplegia 7
  Schizophrenia
  Troyer syndrome
  Juvenile amyotrophic lateral sclerosis
  Frontotemporal dementia
  Hereditary spastic paraplegia
  Hereditary spastic paraplegia 15
  Peripheral neuropathy
• UniProt ID: SPTCS_HUMAN
• Pfam ID: PF14649
• Sequence:
  MAAEEGVASAASAGGSWGTAAMGRVLPMLLVPVPAEAMGQLGSRAQLRTQPEALGSLTAA
  GSLQVLSLTPGSRGGGRCCLEGPFWHFLWEDSRNSSTPTEKPKLLALGENYELLIYEFNL
  KDGRCDATILYSCSREALQKLIDDQDISISLLSLRILSFHNNTSLLFINKCVILHIIFPE
  RDAAIRVLNCFTLPLPAQAVDMIIDTQLCRGILFVLSSLGWIYIFDVVDGTYVAHVDLAL
  HKEDMCNEQQQEPAKISSFTSLKVSQDLDVAVIVSSSNSAVALNLNLYFRQHPGHLLCER
  ILEDLPIQGPKGVDEDDPVNSAYNMKLAKFSFQIDRSWKAQLSSLNETIKNSKLEVSCCA
  PWFQDILHLESPESGNHSTSVQSWAFIPQDIMHGQYNVLQKDHAKTSDPGRSWKIMHISE
  QEEPIELKCVSVTGFTALFTWEVERMGYTITLWDLETQGMQCFSLGTKCIPVDSSGDQQL
  CFVLTENGLSLILFGLTQEEFLNRLMIHGSASTVDTLCHLNGWGRCSIPIHALEAGIENR
  QLDTVNFFLKSKENLFNPSSKSSVSDQFDHLSSHLYLRNVEELIPALDLLCSAIRESYSE
  PQSKHFSEQLLNLTLSFLNNQIKELFIHTEELDEHLQKGVNILTSYINELRTFMIKFPWK
  LTDAIDEYDVHENVPKVKESNIWKKLSFEEVIASAILNNKIPEAQTFFRIDSHSAQKLEE
  LIGIGLNLVFDNLKKNNIKEASELLKNMGFDVKGQLLKICFYTTNKNIRDFLVEILKEKN
  YFSEKEKRTIDFVHQVEKLYLGHFQENMQIQSFPRYWIKEQDFFKHKSVLDSFLKYDCKD
  EFNKQDHRIVLNWALWWDQLTQESILLPRISPEEYKSYSPEALWRYLTARHDWLNIILWI
  GEFQTQHSYASLQQNKWPLLTVDVINQNTSCNNYMRNEILDKLARNGVFLASELEDFECF
  LLRLSRIGGVIQDTLPVQNYKTKEGWDFHSQFILYCLEHSLQHLLYVYLDCYKLSPENCP
  FLEKKELHEAHPWFEFLVQCRQVASNLTDPKLIFQASLANAQILIPTNQASVSSMLLEGH
  TLLALATTMYSPGGVSQVVQNEENENCLKKVDPQLLKMALTPYPKLKTALFPQCTPPSVL
  PSDITIYHLIQSLSPFDPSRLFGWQSANTLAIGDAWSHLPHFSSPDLVNKYAIVERLNFA
  YYLHNGRPSFAFGTFLVQELIKSKTPKQLIQQVGNEAYVIGLSSFHIPSIGAACVCFLEL
  LGLDSLKLRVDMKVANIILSYKCRNEDAQYSFIRESVAEKLSKLADGEKTTTEELLVLLE
  EGTWNSIQQQEIKRLSSESSSQWALVVQFCRLHNMKLSISYLRECAKANDWLQFIIHSQL
  HNYHPAEVKSLIQYFSPVIQDHLRLAFENLPSVPTSKMDSDQVCNKCPQELQGSKQEMTD
  LFEILLQCSEEPDSWHWLLVEAVKQQAPILSVLASCLQGASAISCLCVWIITSVEDNVAT
  EAMGHIQDSTEDHTWNLEDLSVIWRTLLTRQKSKTLIRGFQLFFKDSPLLLVMEMYELCM
  FFRNYKEAEAKLLEFQKSLETLNTAATKVHPVIPAMWLEDQVCFLLKLMLQQCKTQYELG
  KLLQLFVEREHLFSDGPDVKKLCILCQILKDTSIAINHTIITSYSIENLQHECRSILERL
  QTDGQFALARRVAELAELPVDNLVIKEITQEMQTLKHIEQWSLKQARIDFWKKCHENFKK
  NSISSKAASSFFSTQAHVACEHPTGWSSMEERHLLLTLAGHWLAQEDVVPLDKLEELEKQ
  IWLCRITQHTLGRNQEETEPRFSRQISTSGELSFDSLASEFSFSKLAALNTSKYLELNSL
  PSKETCENRLDWKEQESLNFLIGRLLDDGCVHEASRVCRYFHFYNPDVALVLHCRALASG
  EASMEDLHPEIHALLQSAELLEEEAPDIPLRRVHSTSSLDSQKFVTVPSSNEVVTNLEVL
  TSKCLHGKNYCRQVLCLYDLAKELGCSYTDVAAQDGEAMLRKILASQQPDRCKRAQAFIS
  TQGLKPDTVAELVAEEVTRELLTSSQGTGHKQMFNPTEESQTFLQLTTLCQDRTLVGMKL
  LDKISSVPHGELSCTTELLILAHHCFTLTCHMEGIIRVLQAAHMLTDNHLAPSEEYGLVV
  RLLTGIGRYNEMTYIFDLLHKKHYFEVLMRKKLDPSGTLKTALLDYIKRCRPGDSEKHNM
  IALCFSMCREIGENHEAAARIQLKLIESQPWEDSLKDGHQLKQLLLKALTLMLDAAESYA
  KDSCVRQAQHCQRLTKLITLQIHFLNTGQNTMLINLGRHKLMDCILALPRFYQASIVAEA
  YDFVPDWAEILYQQVILKGDFNYLEEFKQQRLLKSSIFEEISKKYKQHQPTDMVMENLKK
  LLTYCEDVYLYYKLAYEHKFYEIVNVLLKDPQTGCCLKDMLAG
• Function: May play a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport.
• Tissue Specificity: Expressed in all structures of brain, with a high expression in cerebellum. Expressed in cortical projection neurons.
• KEGG Pathway:
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis	DISF7HVM	Definitive	Biomarker	[1]
Cognitive impairment	DISH2ERD	Definitive	Biomarker	[2]
Hereditary spastic paraplegia 11	DIS8K8V4	Definitive	Autosomal recessive	[3]
Paraplegia	DISSKWBI	Definitive	Genetic Variation	[4]
Amyotrophic lateral sclerosis type 2, juvenile	DISYFHD8	Strong	Genetic Variation	[5]
Amyotrophic lateral sclerosis type 5	DIS4ZW1V	Strong	Autosomal recessive	[6]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[7]
Cerebrotendinous xanthomatosis	DIST9FNK	Strong	Genetic Variation	[8]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[9]
Charcot-Marie-Tooth disease axonal type 2X	DISY4RUB	Strong	Autosomal recessive	[6]
Complex hereditary spastic paraplegia	DIS9KXQY	Strong	Genetic Variation	[10]
Dementia	DISXL1WY	Strong	Genetic Variation	[7]
Epilepsy	DISBB28L	Strong	Genetic Variation	[11]
Hereditary spastic paraplegia 4	DISFUYL2	Strong	Genetic Variation	[8]
Intellectual disability	DISMBNXP	Strong	Biomarker	[7]
Juvenile-onset Parkinson disease	DISNT5BI	Strong	Genetic Variation	[12]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[13]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[14]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[15]
Polyneuropathy	DISB9G3W	Strong	Biomarker	[16]
Relapsing-remitting multiple sclerosis	DISSXFCF	Strong	Genetic Variation	[14]
Tarsal-carpal coalition syndrome	DISY90L2	Strong	Biomarker	[17]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[8]
Axonal neuropathy	DIS5S2BC	moderate	Genetic Variation	[18]
Bipolar disorder	DISAM7J2	moderate	CausalMutation	[19]
Hereditary spastic paraplegia 7	DIS4A678	moderate	Genetic Variation	[20]
Schizophrenia	DISSRV2N	moderate	CausalMutation	[19]
Troyer syndrome	DISA9RYJ	moderate	Genetic Variation	[20]
Juvenile amyotrophic lateral sclerosis	DISKDZC9	Supportive	Autosomal recessive	[21]
Frontotemporal dementia	DISKYHXL	Limited	Genetic Variation	[22]
Hereditary spastic paraplegia	DISGZQV1	Limited	Biomarker	[23]
Hereditary spastic paraplegia 15	DIS436G5	Limited	Genetic Variation	[4]
Peripheral neuropathy	DIS7KN5G	Limited	Biomarker	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Spatacsin (SPG11).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Spatacsin (SPG11).	[26]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Spatacsin (SPG11).	[27]
Methotrexate	DM2TEOL	Approved	Methotrexate affects the expression of Spatacsin (SPG11).	[28]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Spatacsin (SPG11).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Spatacsin (SPG11).	[31]

1 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 Spatacsin (SPG11).	[30]

References

• [1] Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions.Brain. 2016 Jun;139(Pt 6):1723-34. doi: 10.1093/brain/aww061. Epub 2016 Mar 25.
• [2] Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration.Neurobiol Dis. 2017 Jun;102:21-37. doi: 10.1016/j.nbd.2017.02.007. Epub 2017 Feb 22.
• [3] 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.
• [4] Kjellin syndrome: long-term neuro-ophthalmologic follow-up and novel mutations in the SPG11 gene.Ophthalmology. 2011 Mar;118(3):564-73. doi: 10.1016/j.ophtha.2010.07.024. Epub 2010 Oct 29.
• [5] Mutations in FUS are the most frequent genetic cause in juvenile sporadic ALS patients of Chinese origin.Amyotroph Lateral Scler Frontotemporal Degener. 2016;17(3-4):249-52. doi: 10.3109/21678421.2016.1143012. Epub 2016 Mar 14.
• [6] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [7] Novel Compound Heterozygous Spatacsin Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia.Neurodegener Dis. 2016;16(5-6):373-81. doi: 10.1159/000444715. Epub 2016 Jun 18.
• [8] Are Cognitive Changes in Hereditary Spastic Paraplegias Restricted to Complicated Forms?.Front Neurol. 2019 May 24;10:508. doi: 10.3389/fneur.2019.00508. eCollection 2019.
• [9] High Frequency of Pathogenic Rearrangements in SPG11 and Extensive Contribution of Mutational Hotspots and Founder Alleles.Hum Mutat. 2016 Jul;37(7):703-9. doi: 10.1002/humu.23000. Epub 2016 Apr 28.
• [10] Monozygotic twins with a new compound heterozygous SPG11 mutation and different disease expression.J Neurol Sci. 2017 Oct 15;381:265-268. doi: 10.1016/j.jns.2017.09.005. Epub 2017 Sep 5.
• [11] Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48.Brain. 2014 Jul;137(Pt 7):1907-20. doi: 10.1093/brain/awu121. Epub 2014 May 15.
• [12] Novel mutations in SPG11 cause hereditary spastic paraplegia associated with early-onset levodopa-responsive Parkinsonism.Mov Disord. 2011 Feb 15;26(3):553-6. doi: 10.1002/mds.23552. Epub 2011 Mar 4.
• [13] Inheritance of frontotemporal dementia.Arch Neurol. 1999 Jul;56(7):817-22. doi: 10.1001/archneur.56.7.817.
• [14] A rare case of SPG11 mutation with multiple sclerosis.Rev Neurol (Paris). 2016 Jun-Jul;172(6-7):389-91. doi: 10.1016/j.neurol.2016.03.006. Epub 2016 May 11.
• [15] SPG11-related parkinsonism: Clinical profile, molecular imaging and l-dopa response.Mov Disord. 2018 Oct;33(10):1650-1656. doi: 10.1002/mds.27491. Epub 2018 Oct 10.
• [16] Expanding the clinical spectrum of SPG11 gene mutations in recessive hereditary spastic paraplegia with thin corpus callosum.Eur J Med Genet. 2011 Jan-Feb;54(1):82-5. doi: 10.1016/j.ejmg.2010.10.006. Epub 2010 Nov 12.
• [17] A case of spastic paraplegia-15 with a novel pathogenic variant in ZFYVE26 gene.Int J Neurosci. 2019 Dec;129(12):1198-1202. doi: 10.1080/00207454.2019.1653293. Epub 2019 Aug 19.
• [18] ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. Brain. 2016 Jan;139(Pt 1):73-85. doi: 10.1093/brain/awv320. Epub 2015 Nov 10.
• [19] SPG11 mutations cause Kjellin syndrome, a hereditary spastic paraplegia with thin corpus callosum and central retinal degeneration.Am J Med Genet B Neuropsychiatr Genet. 2009 Oct 5;150B(7):984-92. doi: 10.1002/ajmg.b.30928.
• [20] Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance.J Neurol Sci. 2012 Jul 15;318(1-2):1-18. doi: 10.1016/j.jns.2012.03.025. Epub 2012 May 1.
• [21] Amyotrophic lateral sclerosis: an update on recent genetic insights. J Neurol. 2013 Nov;260(11):2917-27. doi: 10.1007/s00415-013-7112-y. Epub 2013 Oct 2.
• [22] Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort.Neurology. 2015 Dec 15;85(24):2116-25. doi: 10.1212/WNL.0000000000002220. Epub 2015 Nov 18.
• [23] Human SPG11 cerebral organoids reveal cortical neurogenesis impairment.Hum Mol Genet. 2019 Mar 15;28(6):961-971. doi: 10.1093/hmg/ddy397.
• [24] Severe axonal neuropathy is a late manifestation of SPG11.J Neurol. 2016 Nov;263(11):2278-2286. doi: 10.1007/s00415-016-8254-5. Epub 2016 Aug 20.
• [25] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [26] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [27] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [28] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [29] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [30] 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.
• [31] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.