Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9ODC8X)

• DOT Name: Magnesium transporter NIPA1 (NIPA1)
• Synonyms: Non-imprinted in Prader-Willi/Angelman syndrome region protein 1; Spastic paraplegia 6 protein
• Gene Name: NIPA1
• Related Disease:
  Acute myelogenous leukaemia
  Anorexia nervosa cachexia
  Autism
  Epilepsy
  Epilepsy, idiopathic generalized
  Hereditary spastic paraplegia
  Hereditary spastic paraplegia 4
  Hereditary spastic paraplegia 6
  Peripheral neuropathy
  Schizophrenia
  Vascular purpura
  Fetal growth restriction
  Prader-Willi syndrome
  Angelman syndrome
  Paraplegia
• UniProt ID: NIPA1_HUMAN
• Pfam ID: PF05653
• Sequence:
  MGTAAAAAAAAAAAAAGEGARSPSPAAVSLGLGVAVVSSLVNGSTFVLQKKGIVRAKRRG
  TSYLTDIVWWAGTIAMAVGQIGNFLAYTAVPTVLVTPLGALGVPFGSILASYLLKEKLNI
  LGKLGCLLSCAGSVVLIIHSPKSESVTTQAELEEKLTNPVFVGYLCIVLLMLLLLIFWIA
  PAHGPTNIMVYISICSLLGSFTVPSTKGIGLAAQDILHNNPSSQRALCLCLVLLAVLGCS
  IIVQFRYINKALECFDSSVFGAIYYVVFTTLVLLASAILFREWSNVGLVDFLGMACGFTT
  VSVGIVLIQVFKEFNFNLGEMNKSNMKTD
• Function: Acts as a Mg(2+) transporter. Can also transport other divalent cations such as Fe(2+), Sr(2+), Ba(2+), Zn(2+) and Co(2+) but to a much less extent than Mg(2+).
• Tissue Specificity: Widely expressed with highest levels in neuronal tissues.
• Reactome Pathway: Miscellaneous transport and binding events (R-HSA-5223345)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Anorexia nervosa cachexia	DISFO5RQ	Strong	Biomarker	[2]
Autism	DISV4V1Z	Strong	Biomarker	[2]
Epilepsy	DISBB28L	Strong	Genetic Variation	[3]
Epilepsy, idiopathic generalized	DISODZC9	Strong	Biomarker	[3]
Hereditary spastic paraplegia	DISGZQV1	Strong	Genetic Variation	[4]
Hereditary spastic paraplegia 4	DISFUYL2	Strong	Genetic Variation	[5]
Hereditary spastic paraplegia 6	DISVB8NO	Strong	Autosomal dominant	[6]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[7]
Schizophrenia	DISSRV2N	Strong	Biomarker	[2]
Vascular purpura	DIS6ZZMF	Strong	Biomarker	[8]
Fetal growth restriction	DIS5WEJ5	moderate	Biomarker	[9]
Prader-Willi syndrome	DISYWMLU	moderate	Altered Expression	[10]
Angelman syndrome	DIS4QVXO	Disputed	Genetic Variation	[11]
Paraplegia	DISSKWBI	Limited	Genetic Variation	[12]

9 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 Magnesium transporter NIPA1 (NIPA1).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Magnesium transporter NIPA1 (NIPA1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Magnesium transporter NIPA1 (NIPA1).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Magnesium transporter NIPA1 (NIPA1).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Magnesium transporter NIPA1 (NIPA1).	[17]
Marinol	DM70IK5	Approved	Marinol increases the expression of Magnesium transporter NIPA1 (NIPA1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Magnesium transporter NIPA1 (NIPA1).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Magnesium transporter NIPA1 (NIPA1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Magnesium transporter NIPA1 (NIPA1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Magnesium transporter NIPA1 (NIPA1).	[21]

References

• [1] SPG6 supports development of acute myeloid leukemia by regulating BMPR2-Smad-Bcl-2/Bcl-xl signaling.Biochem Biophys Res Commun. 2018 Jun 18;501(1):220-225. doi: 10.1016/j.bbrc.2018.04.220. Epub 2018 May 3.
• [2] Microduplications at the 15q11.2 BP1-BP2 locus are enriched in patients with anorexia nervosa.J Psychiatr Res. 2019 Jun;113:34-38. doi: 10.1016/j.jpsychires.2019.01.021. Epub 2019 Jan 29.
• [3] NIPA1 mutation in complex hereditary spastic paraplegia with epilepsy.Eur J Neurol. 2011 Sep;18(9):1197-9. doi: 10.1111/j.1468-1331.2011.03359.x. Epub 2011 Feb 22.
• [4] Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort.Neurobiol Aging. 2019 Feb;74:234.e9-234.e15. doi: 10.1016/j.neurobiolaging.2018.09.012. Epub 2018 Sep 22.
• [5] Isolation of CAG/CTG repeats from within the chromosome 2p21-p24 locus for autosomal dominant spastic paraplegia (SPG4) by YAC fragmentation.Hum Genet. 1999 Sep;105(3):217-25. doi: 10.1007/s004390051092.
• [6] Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families. Hum Mutat. 2005 Feb;25(2):135-41. doi: 10.1002/humu.20126.
• [7] Expansion of the phenotypic spectrum of SPG6 caused by mutation in NIPA1.Clin Neurol Neurosurg. 2011 Jul;113(6):480-2. doi: 10.1016/j.clineuro.2011.02.011. Epub 2011 Mar 17.
• [8] TDP-43 pathology in a case of hereditary spastic paraplegia with a NIPA1/SPG6 mutation.Acta Neuropathol. 2012 Aug;124(2):285-91. doi: 10.1007/s00401-012-0947-y.
• [9] Prenatal diagnosis of a familial 15q11.2 (BP1-BP2) microdeletion encompassing TUBGCP5, CYFIP1, NIPA2 and NIPA1 in a fetus with ventriculomegaly, microcephaly and intrauterine growth restriction on prenatal ultrasound.Taiwan J Obstet Gynecol. 2018 Oct;57(5):730-733. doi: 10.1016/j.tjog.2018.08.022.
• [10] Expression of 4 genes between chromosome 15 breakpoints 1 and 2 and behavioral outcomes in Prader-Willi syndrome.Pediatrics. 2006 Oct;118(4):e1276-83. doi: 10.1542/peds.2006-0424. Epub 2006 Sep 18.
• [11] Clinical and genetic aspects of the 15q11.2 BP1-BP2 microdeletion disorder.J Intellect Disabil Res. 2017 Jun;61(6):568-579. doi: 10.1111/jir.12382. Epub 2017 Apr 7.
• [12] NIPA1 (SPG6) mutations are a rare cause of autosomal dominant spastic paraplegia in Europe.Neurogenetics. 2007 Apr;8(2):155-7. doi: 10.1007/s10048-006-0074-9. Epub 2007 Jan 5.
• [13] 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.
• [14] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [15] 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.
• [16] 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.
• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [22] 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.