Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT455EIC)

• DOT Name: Major facilitator superfamily domain-containing protein 8 (MFSD8)
• Synonyms: Ceroid-lipofuscinosis neuronal protein 7
• Gene Name: MFSD8
• Related Disease:
  Cone-rod dystrophy
  Cone-rod dystrophy 2
  Frontotemporal dementia
  Neuronal ceroid lipofuscinosis
  Neuronal ceroid lipofuscinosis 7
  Pick disease
  CLN2 Batten disease
  Disorder of orbital region
  Hereditary macular dystrophy
  Late infantile neuronal ceroid lipofuscinosis
  Lysosomal storage disease
  Macular dystrophy with central cone involvement
  Neuronal ceroid lipofuscinosis 8
  Age-related macular degeneration
  Nervous system disease
  Adult neuronal ceroid lipofuscinosis
  Blindness
• UniProt ID: MFSD8_HUMAN
• Pfam ID: PF07690
• Sequence:
  MAGLRNESEQEPLLGDTPGSREWDILETEEHYKSRWRSIRILYLTMFLSSVGFSVVMMSI
  WPYLQKIDPTADTSFLGWVIASYSLGQMVASPIFGLWSNYRPRKEPLIVSILISVAANCL
  YAYLHIPASHNKYYMLVARGLLGIGAGNVAVVRSYTAGATSLQERTSSMANISMCQALGF
  ILGPVFQTCFTFLGEKGVTWDVIKLQINMYTTPVLLSAFLGILNIILILAILREHRVDDS
  GRQCKSINFEEASTDEAQVPQGNIDQVAVVAINVLFFVTLFIFALFETIITPLTMDMYAW
  TQEQAVLYNGIILAALGVEAVVIFLGVKLLSKKIGERAILLGGLIVVWVGFFILLPWGNQ
  FPKIQWEDLHNNSIPNTTFGEIIIGLWKSPMEDDNERPTGCSIEQAWCLYTPVIHLAQFL
  TSAVLIGLGYPVCNLMSYTLYSKILGPKPQGVYMGWLTASGSGARILGPMFISQVYAHWG
  PRWAFSLVCGIIVLTITLLGVVYKRLIALSVRYGRIQE
• Function: Outward-rectifying chloride channel involved in endolysosomal chloride homeostasis, membrane fusion and function. Conducts chloride currents up to hundreds of picoamperes. Regulates lysosomal calcium content by reducing the lysosomal membrane potential, thereby activating TRPML1 channel and further release of lysosomal calcium ions. Regulates the pH in endolysosomal compartments and may contribute to progressive acidification from endosome to lysosome. Permeable to other halides such as iodide and fluoride ions.
• Tissue Specificity: Expressed at very low levels in all tissues tested.
• KEGG Pathway: Lysosome (hsa04142)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cone-rod dystrophy	DISY9RWN	Definitive	Genetic Variation	[1]
Cone-rod dystrophy 2	DISX2RWY	Definitive	Genetic Variation	[1]
Frontotemporal dementia	DISKYHXL	Definitive	Genetic Variation	[2]
Neuronal ceroid lipofuscinosis	DIS9A4K4	Definitive	Autosomal recessive	[3]
Neuronal ceroid lipofuscinosis 7	DISVZUFT	Definitive	Autosomal recessive	[4]
Pick disease	DISP6X50	Definitive	Genetic Variation	[2]
CLN2 Batten disease	DISZC5YB	Strong	Genetic Variation	[5]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[6]
Hereditary macular dystrophy	DISEYSYY	Strong	Genetic Variation	[6]
Late infantile neuronal ceroid lipofuscinosis	DISI3RIL	Strong	Genetic Variation	[7]
Lysosomal storage disease	DIS6QM6U	Strong	Genetic Variation	[8]
Macular dystrophy with central cone involvement	DISDZB3O	Strong	Autosomal recessive	[6]
Neuronal ceroid lipofuscinosis 8	DISGNC07	Strong	Biomarker	[9]
Age-related macular degeneration	DIS0XS2C	moderate	Genetic Variation	[6]
Nervous system disease	DISJ7GGT	Disputed	Genetic Variation	[10]
Adult neuronal ceroid lipofuscinosis	DIS5UHAA	Limited	Biomarker	[11]
Blindness	DISTIM10	Limited	Genetic Variation	[12]

6 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 Major facilitator superfamily domain-containing protein 8 (MFSD8).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Major facilitator superfamily domain-containing protein 8 (MFSD8).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Major facilitator superfamily domain-containing protein 8 (MFSD8).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Major facilitator superfamily domain-containing protein 8 (MFSD8).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Major facilitator superfamily domain-containing protein 8 (MFSD8).	[17]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Major facilitator superfamily domain-containing protein 8 (MFSD8).	[17]

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 Major facilitator superfamily domain-containing protein 8 (MFSD8).	[18]

References

• [1] MFSD8 gene mutations; evidence for phenotypic heterogeneity.Ophthalmic Genet. 2019 Apr;40(2):141-145. doi: 10.1080/13816810.2019.1592200. Epub 2019 Apr 22.
• [2] Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia.Acta Neuropathol. 2019 Jan;137(1):71-88. doi: 10.1007/s00401-018-1925-9. Epub 2018 Oct 31.
• [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] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [5] Discovery of a CLN7 model of Batten disease in non-human primates.Neurobiol Dis. 2018 Nov;119:65-78. doi: 10.1016/j.nbd.2018.07.013. Epub 2018 Jul 23.
• [6] Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy. Ophthalmology. 2015 Jan;122(1):170-9. doi: 10.1016/j.ophtha.2014.07.040. Epub 2014 Sep 13.
• [7] Rett-like onset in late-infantile neuronal ceroid lipofuscinosis (CLN7) caused by compound heterozygous mutation in the MFSD8 gene and review of the literature data on clinical onset signs.Eur J Paediatr Neurol. 2015 Jan;19(1):78-86. doi: 10.1016/j.ejpn.2014.07.008. Epub 2014 Aug 7.
• [8] Functional characterization of novel MFSD8 pathogenic variants anticipates neurological involvement in juvenile isolated maculopathy.Clin Genet. 2020 Mar;97(3):426-436. doi: 10.1111/cge.13673. Epub 2019 Dec 12.
• [9] CLN6 disease caused by the same mutation originating in Pakistan has varying pathology.Eur J Paediatr Neurol. 2013 Nov;17(6):657-60. doi: 10.1016/j.ejpn.2013.04.011. Epub 2013 Jun 2.
• [10] Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy.Invest Ophthalmol Vis Sci. 2017 Jun 1;58(7):2906-2914. doi: 10.1167/iovs.16-20608.
• [11] Gene disruption of Mfsd8 in mice provides the first animal model for CLN7 disease.Neurobiol Dis. 2014 May;65:12-24. doi: 10.1016/j.nbd.2014.01.003. Epub 2014 Jan 11.
• [12] A novel mutation in the MFSD8 gene in late infantile neuronal ceroid lipofuscinosis.Neurogenetics. 2009 Feb;10(1):73-7. doi: 10.1007/s10048-008-0153-1. Epub 2008 Oct 11.
• [13] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 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.
• [18] 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.