Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR2788Y)

• DOT Name: Atlastin-1 (ATL1)
• Synonyms: EC 3.6.5.-; Brain-specific GTP-binding protein; GTP-binding protein 3; GBP-3; hGBP3; Guanine nucleotide-binding protein 3; Spastic paraplegia 3 protein A
• Gene Name: ATL1
• Related Disease:
  Breast carcinoma
  Dysautonomia
  Hereditary spastic paraplegia 3A
  Metastatic malignant neoplasm
  Neuropathy, hereditary sensory, type 1D
  Adult T-cell leukemia/lymphoma
  Advanced cancer
  Cardiovascular disease
  Chronic kidney disease
  Ductal carcinoma
  Epilepsy
  Focal segmental glomerulosclerosis
  Glomerulosclerosis
  Hereditary sensory and autonomic neuropathy
  Hereditary spastic paraplegia
  Hereditary spastic paraplegia 4
  Intellectual disability
  Motor neurone disease
  Myocardial infarction
  Peripheral neuropathy
  Prostate cancer
  Prostate carcinoma
  Pure hereditary spastic paraplegia
  Restless legs syndrome
  Temporal lobe epilepsy
  Fetal growth restriction
  High blood pressure
  Neurodevelopmental disorder
  Peripheral sensory neuropathies
  Hereditary sensory and autonomic neuropathy type 1
  Amyotrophic lateral sclerosis
  Donohue syndrome
  Lung cancer
  Lung carcinoma
  Movement disorder
  Neoplasm
  Nervous system disease
  Neuroblastoma
  Paraplegia
• UniProt ID: ATLA1_HUMAN
• PDB ID: 3Q5D; 3Q5E; 3QNU; 3QOF; 4IDN; 4IDO; 4IDP; 4IDQ; 6B9D; 6B9E; 6B9F; 6B9G; 6XJN; 7OL3
• EC Number: 3.6.5.-
• Pfam ID: PF02263
• Sequence:
  MAKNRRDRNSWGGFSEKTYEWSSEEEEPVKKAGPVQVLIVKDDHSFELDETALNRILLSE
  AVRDKEVVAVSVAGAFRKGKSFLMDFMLRYMYNQESVDWVGDYNEPLTGFSWRGGSERET
  TGIQIWSEIFLINKPDGKKVAVLLMDTQGTFDSQSTLRDSATVFALSTMISSIQVYNLSQ
  NVQEDDLQHLQLFTEYGRLAMEETFLKPFQSLIFLVRDWSFPYEFSYGADGGAKFLEKRL
  KVSGNQHEELQNVRKHIHSCFTNISCFLLPHPGLKVATNPNFDGKLKEIDDEFIKNLKIL
  IPWLLSPESLDIKEINGNKITCRGLVEYFKAYIKIYQGEELPHPKSMLQATAEANNLAAV
  ATAKDTYNKKMEEICGGDKPFLAPNDLQTKHLQLKEESVKLFRGVKKMGGEEFSRRYLQQ
  LESEIDELYIQYIKHNDSKNIFHAARTPATLFVVIFITYVIAGVTGFIGLDIIASLCNMI
  MGLTLITLCTWAYIRYSGEYRELGAVIDQVAAALWDQGSTNEALYKLYSAAATHRHLYHQ
  AFPTPKSESTEQSEKKKM
• Function: GTPase tethering membranes through formation of trans-homooligomers and mediating homotypic fusion of endoplasmic reticulum membranes. Functions in endoplasmic reticulum tubular network biogenesis. May also regulate Golgi biogenesis. May regulate axonal development.
• Tissue Specificity: Expressed predominantly in the adult and fetal central nervous system. Measurable expression in all tissues examined, although expression in adult brain is at least 50-fold higher than in other tissues. Detected predominantly in pyramidal neurons in the cerebral cortex and the hippocampus of the brain. Expressed in upper and lower motor neurons (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Dysautonomia	DISF4MT6	Definitive	Genetic Variation	[2]
Hereditary spastic paraplegia 3A	DISWGEU6	Definitive	Semidominant	[3]
Metastatic malignant neoplasm	DIS86UK6	Definitive	Altered Expression	[1]
Neuropathy, hereditary sensory, type 1D	DISRHHY6	Definitive	Autosomal dominant	[4]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Genetic Variation	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[7]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[8]
Ductal carcinoma	DIS15EA5	Strong	Altered Expression	[9]
Epilepsy	DISBB28L	Strong	Biomarker	[10]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Biomarker	[11]
Glomerulosclerosis	DISJF20Z	Strong	Biomarker	[11]
Hereditary sensory and autonomic neuropathy	DIS2VOAM	Strong	Biomarker	[12]
Hereditary spastic paraplegia	DISGZQV1	Strong	Genetic Variation	[13]
Hereditary spastic paraplegia 4	DISFUYL2	Strong	Genetic Variation	[14]
Intellectual disability	DISMBNXP	Strong	Biomarker	[15]
Motor neurone disease	DISUHWUI	Strong	Genetic Variation	[16]
Myocardial infarction	DIS655KI	Strong	Biomarker	[17]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[18]
Prostate cancer	DISF190Y	Strong	Altered Expression	[19]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[19]
Pure hereditary spastic paraplegia	DIS8X71E	Strong	Genetic Variation	[20]
Restless legs syndrome	DISNWY00	Strong	Biomarker	[21]
Temporal lobe epilepsy	DISNOPXX	Strong	Altered Expression	[10]
Fetal growth restriction	DIS5WEJ5	moderate	Biomarker	[22]
High blood pressure	DISY2OHH	moderate	Altered Expression	[23]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[24]
Peripheral sensory neuropathies	DISYWI6M	moderate	Genetic Variation	[25]
Hereditary sensory and autonomic neuropathy type 1	DISLSPO4	Supportive	Autosomal dominant	[26]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Genetic Variation	[27]
Donohue syndrome	DISI822K	Limited	Biomarker	[28]
Lung cancer	DISCM4YA	Limited	Biomarker	[6]
Lung carcinoma	DISTR26C	Limited	Biomarker	[6]
Movement disorder	DISOJJ2D	Limited	Genetic Variation	[29]
Neoplasm	DISZKGEW	Limited	Biomarker	[30]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[31]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[32]
Paraplegia	DISSKWBI	Limited	Genetic Variation	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Atlastin-1 (ATL1).	[34]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Atlastin-1 (ATL1).	[35]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Atlastin-1 (ATL1).	[36]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Atlastin-1 (ATL1).	[37]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Atlastin-1 (ATL1).	[38]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Atlastin-1 (ATL1).	[39]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Atlastin-1 (ATL1).	[40]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Atlastin-1 (ATL1).	[41]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Atlastin-1 (ATL1).	[43]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Atlastin-1 (ATL1).	[44]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Atlastin-1 (ATL1).	[45]
Propanoic Acid	DM9TN2W	Investigative	Propanoic Acid decreases the expression of Atlastin-1 (ATL1).	[46]

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 decreases the methylation of Atlastin-1 (ATL1).	[42]

References

• [1] BMPR2 loss in fibroblasts promotes mammary carcinoma metastasis via increased inflammation.Mol Oncol. 2015 Jan;9(1):179-91. doi: 10.1016/j.molonc.2014.08.004. Epub 2014 Aug 23.
• [2] Novel mutation in the ATL1 with autosomal dominant hereditary spastic paraplegia presented as dysautonomia.Auton Neurosci. 2014 Oct;185:141-3. doi: 10.1016/j.autneu.2014.06.001. Epub 2014 Jun 9.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] 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.
• [5] Methylation analysis of the adenomatous polyposis coli (APC) gene in adult T-cell leukemia/lymphoma.Leuk Res. 2005 Jan;29(1):47-51. doi: 10.1016/j.leukres.2004.05.004.
• [6] The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.Nature. 2019 Nov;575(7784):688-692. doi: 10.1038/s41586-019-1705-2. Epub 2019 Oct 21.
• [7] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [8] Cinacalcet attenuated bone loss via inhibiting parathyroid hormone-induced endothelial-to-adipocyte transition in chronic kidney disease rats.Ann Transl Med. 2019 Jul;7(14):312. doi: 10.21037/atm.2019.06.44.
• [9] Tenascin C is a prognostic determinant and potential cancer-associated fibroblasts marker for breast ductal carcinoma.Exp Mol Pathol. 2017 Apr;102(2):262-267. doi: 10.1016/j.yexmp.2017.02.012. Epub 2017 Feb 20.
• [10] Atlastin-1 modulates seizure activity and neuronal excitability.CNS Neurosci Ther. 2020 Mar;26(3):385-393. doi: 10.1111/cns.13258. Epub 2019 Nov 14.
• [11] Clinical significance of fibroblast-specific protein-1 expression on podocytes in patients with focal segmental glomerulosclerosis.Nephron Clin Pract. 2012;120(1):c1-7. doi: 10.1159/000334184. Epub 2011 Nov 23.
• [12] ARL6IP1 mutation causes congenital insensitivity to pain, acromutilation and spastic paraplegia.Clin Genet. 2018 Jan;93(1):169-172. doi: 10.1111/cge.13048. Epub 2017 Aug 31.
• [13] Atlastin-1 regulates morphology and function of endoplasmic reticulum in dendrites.Nat Commun. 2019 Feb 4;10(1):568. doi: 10.1038/s41467-019-08478-6.
• [14] Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia.BMC Neurol. 2010 Oct 8;10:89. doi: 10.1186/1471-2377-10-89.
• [15] The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes.Neurogenetics. 2018 May;19(2):111-121. doi: 10.1007/s10048-018-0545-9. Epub 2018 Apr 24.
• [16] Disease-Causing Variants in the ATL1 Gene Are a Rare Cause of Hereditary Spastic Paraplegia among Czech Patients.Ann Hum Genet. 2017 Nov;81(6):249-257. doi: 10.1111/ahg.12206. Epub 2017 Jul 23.
• [17] Identification of a pro-angiogenic functional role for FSP1-positive fibroblast subtype in wound healing.Nat Commun. 2019 Jul 9;10(1):3027. doi: 10.1038/s41467-019-10965-9.
• [18] Hereditary spastic paraplegia and axonal motor neuropathy caused by a novel SPG3A de novo mutation.Brain Dev. 2010 Aug;32(7):592-4. doi: 10.1016/j.braindev.2009.08.003. Epub 2009 Sep 6.
• [19] Tenascin-C is a potential cancer-associated fibroblasts marker and predicts poor prognosis in prostate cancer.Biochem Biophys Res Commun. 2017 May 6;486(3):607-612. doi: 10.1016/j.bbrc.2017.03.021. Epub 2017 Mar 21.
• [20] Mutation analysis of four Chinese families with pure hereditary spastic paraplegia: pseudo- X-linked dominant inheritance and male lethality due to a novel ATL1 mutation.Genet Mol Res. 2015 Nov 23;14(4):14690-7. doi: 10.4238/2015.November.18.33.
• [21] ATL1 and REEP1 mutations in hereditary and sporadic upper motor neuron syndromes.J Neurol. 2013 Mar;260(3):869-75. doi: 10.1007/s00415-012-6723-z. Epub 2012 Oct 30.
• [22] Activation of glucose transport by a natural mutation in the human insulin receptor.Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):60-4. doi: 10.1073/pnas.90.1.60.
• [23] Klotho and PPAR Gamma Activation Mediate the Renoprotective Effect of Losartan in the 5/6 Nephrectomy Model.Front Physiol. 2018 Aug 2;9:1033. doi: 10.3389/fphys.2018.01033. eCollection 2018.
• [24] Hereditary spastic paraplegia.Neurol Clin. 2002 Aug;20(3):711-26. doi: 10.1016/s0733-8619(02)00007-5.
• [25] The N355K atlastin 1 mutation is associated with hereditary sensory neuropathy and pyramidal tract features.Eur J Neurol. 2012 Jul;19(7):992-8. doi: 10.1111/j.1468-1331.2012.03665.x. Epub 2012 Feb 16.
• [26] Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I. Am J Hum Genet. 2011 Jan 7;88(1):99-105. doi: 10.1016/j.ajhg.2010.12.003. Epub 2010 Dec 30.
• [27] Complex phenotype in an Italian family with a novel mutation in SPG3A.J Neurol. 2010 Mar;257(3):328-31. doi: 10.1007/s00415-009-5311-3. Epub 2009 Sep 19.
• [28] Prenatal analysis of the insulin receptor gene in a family with leprechaunism.Prenat Diagn. 1995 Nov;15(11):1070-4. doi: 10.1002/pd.1970151113.
• [29] Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia.Hum Mutat. 2013 Jun;34(6):860-3. doi: 10.1002/humu.22309. Epub 2013 Apr 5.
• [30] Lipoxin-Induced Phenotypic Changes in CD115(+)LY6C(hi) Monocytes TAM Precursors Inhibits Tumor Development.Front Oncol. 2019 Jun 19;9:540. doi: 10.3389/fonc.2019.00540. eCollection 2019.
• [31] A hereditary spastic paraplegia-associated atlastin variant exhibits defective allosteric coupling in the catalytic core.J Biol Chem. 2018 Jan 12;293(2):687-700. doi: 10.1074/jbc.RA117.000380. Epub 2017 Nov 27.
• [32] Cancer-Associated Fibroblasts Share Characteristics and Protumorigenic Activity with Mesenchymal Stromal Cells.Cancer Res. 2017 Sep 15;77(18):5142-5157. doi: 10.1158/0008-5472.CAN-16-2586. Epub 2017 Jul 7.
• [33] Homozygous mutation in Atlastin GTPase 1 causes recessive hereditary spastic paraplegia.J Hum Genet. 2016 Jun;61(6):571-3. doi: 10.1038/jhg.2016.6. Epub 2016 Feb 18.
• [34] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [35] 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.
• [36] 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.
• [37] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [38] 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.
• [39] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [40] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [41] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [42] 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.
• [43] 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.
• [44] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [45] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.
• [46] Propionic acid induces mitochondrial dysfunction and affects gene expression for mitochondria biogenesis and neuronal differentiation in SH-SY5Y cell line. Neurotoxicology. 2019 Dec;75:116-122. doi: 10.1016/j.neuro.2019.09.009. Epub 2019 Sep 14.