Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8BAM04)

• DOT Name: Alsin (ALS2)
• Synonyms: Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 6 protein; Amyotrophic lateral sclerosis 2 protein
• Gene Name: ALS2
• Related Disease:
  ALS2-related motor neuron disease
  Amyotrophic lateral sclerosis type 2, juvenile
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Familial amyotrophic lateral sclerosis
  Hereditary spastic paraplegia
  Infantile-onset ascending hereditary spastic paralysis
  Juvenile primary lateral sclerosis
  Lateral sclerosis
  Motor neurone disease
  Movement disorder
  Papillon-Lefevre disease
  Vascular purpura
  Juvenile amyotrophic lateral sclerosis
  Complex hereditary spastic paraplegia
  Cardiomyopathy
  Paraplegia
• UniProt ID: ALS2_HUMAN
• Pfam ID: PF02493 ; PF00415 ; PF00621 ; PF02204
• Sequence:
  MDSKKRSSTEAEGSKERGLVHIWQAGSFPITPERLPGWGGKTVLQAALGVKHGVLLTEDG
  EVYSFGTLPWRSGPVEICPSSPILENALVGQYVITVATGSFHSGAVTDNGVAYMWGENSA
  GQCAVANQQYVPEPNPVSIADSEASPLLAVRILQLACGEEHTLALSISREIWAWGTGCQL
  GLITTAFPVTKPQKVEHLAGRVVLQVACGAFHSLALVQCLPSQDLKPVPERCNQCSQLLI
  TMTDKEDHVIISDSHCCPLGVTLTESQAENHASTALSPSTETLDRQEEVFENTLVANDQS
  VATELNAVSAQITSSDAMSSQQNVMGTTEISSARNIPSYPDTQAVNEYLRKLSDHSVRED
  SEHGEKPVPSQPLLEEAIPNLHSPPTTSTSALNSLVVSCASAVGVRVAATYEAGALSLKK
  VMNFYSTTPCETGAQAGSSAIGPEGLKDSREEQVKQESMQGKKSSSLVDIREEETEGGSR
  RLSLPGLLSQVSPRLLRKAARVKTRTVVLTPTYSGEADALLPSLRTEVWTWGKGKEGQLG
  HGDVLPRLQPLCVKCLDGKEVIHLEAGGYHSLALTAKSQVYSWGSNTFGQLGHSDFPTTV
  PRLAKISSENGVWSIAAGRDYSLFLVDTEDFQPGLYYSGRQDPTEGDNLPENHSGSKTPV
  LLSCSKLGYISRVTAGKDSYLALVDKNIMGYIASLHELATTERRFYSKLSDIKSQILRPL
  LSLENLGTTTTVQLLQEVASRFSKLCYLIGQHGASLSSFLHGVKEARSLVILKHSSLFLD
  SYTEYCTSITNFLVMGGFQLLAKPAIDFLNKNQELLQDLSEVNDENTQLMEILNTLFFLP
  IRRLHNYAKVLLKLATCFEVASPEYQKLQDSSSCYECLALHLGRKRKEAEYTLGFWKTFP
  GKMTDSLRKPERRLLCESSNRALSLQHAGRFSVNWFILFNDALVHAQFSTHHVFPLATLW
  AEPLSEEAGGVNGLKITTPEEQFTLISSTPQEKTKWLRAISQAVDQALRGMSDLPPYGSG
  SSVQRQEPPISRSAKYTFYKDPRLKDATYDGRWLSGKPHGRGVLKWPDGKMYSGMFRNGL
  EDGYGEYRIPNKAMNKEDHYVGHWKEGKMCGQGVYSYASGEVFEGCFQDNMRHGHGLLRS
  GKLTSSSPSMFIGQWVMDKKAGYGVFDDITRGEKYMGMWQDDVCQGNGVVVTQFGLYYEG
  NFHLNKMMGNGVLLSEDDTIYEGEFSDDWTLSGKGTLTMPNGDYIEGYFSGEWGSGIKIT
  GTYFKPSLYESDKDRPKVFRKLGNLAVPADEKWKAVFDECWRQLGCEGPGQGEVWKAWDN
  IAVALTTSRRQHRDSPEILSRSQTQTLESLEFIPQHVGAFSVEKYDDIRKYLIKACDTPL
  HPLGRLVETLVAVYRMTYVGVGANRRLLQEAVKEIKSYLKRIFQLVRFLFPELPEEGSTI
  PLSAPLPTERKSFCTGKSDSRSESPEPGYVVTSSGLLLPVLLPRLYPPLFMLYALDNDRE
  EDIYWECVLRLNKQPDIALLGFLGVQRKFWPATLSILGESKKVLPTTKDACFASAVECLQ
  QISTTFTPSDKLKVIQQTFEEISQSVLASLHEDFLWSMDDLFPVFLYVVLRARIRNLGSE
  VHLIEDLMDPYLQHGEQGIMFTTLKACYYQIQREKLN
• Function: May act as a GTPase regulator. Controls survival and growth of spinal motoneurons.
• KEGG Pathway:
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  RAC1 GTPase cycle (R-HSA-9013149)
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
ALS2-related motor neuron disease	DIS1QTFG	Definitive	Autosomal recessive	[1]
Amyotrophic lateral sclerosis type 2, juvenile	DISYFHD8	Definitive	Autosomal recessive	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Biomarker	[4]
Familial amyotrophic lateral sclerosis	DISWZ9CJ	Strong	Genetic Variation	[5]
Hereditary spastic paraplegia	DISGZQV1	Strong	Genetic Variation	[6]
Infantile-onset ascending hereditary spastic paralysis	DISFBV9C	Strong	Autosomal recessive	[7]
Juvenile primary lateral sclerosis	DIS4OCLQ	Strong	Autosomal recessive	[7]
Lateral sclerosis	DISH30B8	Strong	Genetic Variation	[8]
Motor neurone disease	DISUHWUI	Strong	Genetic Variation	[9]
Movement disorder	DISOJJ2D	Strong	Biomarker	[10]
Papillon-Lefevre disease	DIS3R7KX	Strong	Genetic Variation	[11]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[12]
Juvenile amyotrophic lateral sclerosis	DISKDZC9	Supportive	Autosomal recessive	[13]
Complex hereditary spastic paraplegia	DIS9KXQY	Disputed	Genetic Variation	[14]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[15]
Paraplegia	DISSKWBI	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Alsin (ALS2).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Alsin (ALS2).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Alsin (ALS2).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Alsin (ALS2).	[20]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Alsin (ALS2).	[21]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Alsin (ALS2).	[22]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Alsin (ALS2).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Alsin (ALS2).	[26]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Alsin (ALS2).	[27]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Alsin (ALS2).	[28]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Alsin (ALS2).	[29]

2 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 Alsin (ALS2).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Alsin (ALS2).	[25]

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] The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet. 2001 Oct;29(2):160-5. doi: 10.1038/ng1001-160.
• [3] Whole-Transcriptome Analysis of APP/PS1 Mouse Brain and Identification of circRNA-miRNA-mRNA Networks to Investigate AD Pathogenesis.Mol Ther Nucleic Acids. 2019 Dec 6;18:1049-1062. doi: 10.1016/j.omtn.2019.10.030. Epub 2019 Nov 6.
• [4] Theme 1 Epidemiology and informatics.Amyotroph Lateral Scler Frontotemporal Degener. 2019 Nov;20(sup1):101-113. doi: 10.1080/21678421.2019.1646989.
• [5] A novel Akt/PKB-interacting protein promotes cell adhesion and inhibits familial amyotrophic lateral sclerosis-linked mutant SOD1-induced neuronal death via inhibition of PP2A-mediated dephosphorylation of Akt/PKB.Cell Signal. 2008 Mar;20(3):493-505. doi: 10.1016/j.cellsig.2007.11.004. Epub 2007 Nov 17.
• [6] A novel homozygous mutation in ALS2 gene in four siblings with infantile-onset ascending hereditary spastic paralysis.Eur J Med Genet. 2014 May-Jun;57(6):275-8. doi: 10.1016/j.ejmg.2014.03.006. Epub 2014 Apr 3.
• [7] 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.
• [8] A novel ALS2 splice-site mutation in a Cypriot juvenile-onset primary lateral sclerosis family. Neurology. 2009 Jan 6;72(1):28-32. doi: 10.1212/01.wnl.0000338530.77394.60.
• [9] Altered oligomeric states in pathogenic ALS2 variants associated with juvenile motor neuron diseases cause loss of ALS2-mediated endosomal function.J Biol Chem. 2018 Nov 2;293(44):17135-17153. doi: 10.1074/jbc.RA118.003849. Epub 2018 Sep 17.
• [10] ALS2/alsin knockout mice and motor neuron diseases.Neurodegener Dis. 2008;5(6):359-66. doi: 10.1159/000151295. Epub 2008 Aug 20.
• [11] Exome Sequencing Identifies a Mutation (Y740C) in Spastic Paraplegia 7 Gene Associated with Adult-Onset Primary Lateral Sclerosis in a Chinese Family.Eur Neurol. 2019;81(1-2):87-93. doi: 10.1159/000500672. Epub 2019 May 22.
• [12] Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan.Eur J Hum Genet. 2016 Jan;25(1):100-110. doi: 10.1038/ejhg.2016.108. Epub 2016 Sep 7.
• [13] A novel compound heterozygous ALS2 mutation in two Italian siblings with juvenile amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Sep;14(5-6):470-2. doi: 10.3109/21678421.2012.756036. Epub 2013 Jan 3.
• [14] The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function.Brain. 2006 Jul;129(Pt 7):1710-9. doi: 10.1093/brain/awl104. Epub 2006 May 2.
• [15] Effectiveness of whole exome sequencing in unsolved patients with a clinical suspicion of a mitochondrial disorder in Estonia.Mol Genet Metab Rep. 2018 Mar 15;15:80-89. doi: 10.1016/j.ymgmr.2018.03.004. eCollection 2018 Jun.
• [16] The first nonsense mutation in alsin results in a homogeneous phenotype of infantile-onset ascending spastic paralysis with bulbar involvement in two siblings.Clin Genet. 2003 Sep;64(3):210-5. doi: 10.1034/j.1399-0004.2003.00138.x.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] 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.
• [21] 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.
• [22] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [23] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [24] 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.
• [25] 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.
• [26] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [27] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [28] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [29] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.