Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0D4CB5)

• DOT Name: Protein CLN8 (CLN8)
• Gene Name: CLN8
• Related Disease:
  Neuronal ceroid lipofuscinosis
  Neuronal ceroid lipofuscinosis 8
  Absence epilepsy
  CLN2 Batten disease
  Epilepsy
  Intellectual disability
  Late infantile neuronal ceroid lipofuscinosis
  Lysosomal storage disease
  Neuronal ceroid lipofuscinosis 7
  Neuronal ceroid lipofuscinosis 8 northern epilepsy variant
  Non-insulin dependent diabetes
  Pervasive developmental disorder
  Acute myelogenous leukaemia
  Movement disorder
  Rheumatoid arthritis
  Autism spectrum disorder
  Adult neuronal ceroid lipofuscinosis
  Gaucher disease
• UniProt ID: CLN8_HUMAN
• Pfam ID: PF03798
• Sequence:
  MNPASDGGTSESIFDLDYASWGIRSTLMVAGFVFYLGVFVVCHQLSSSLNATYRSLVARE
  KVFWDLAATRAVFGVQSTAAGLWALLGDPVLHADKARGQQNWCWFHITTATGFFCFENVA
  VHLSNLIFRTFDLFLVIHHLFAFLGFLGCLVNLQAGHYLAMTTLLLEMSTPFTCVSWMLL
  KAGWSESLFWKLNQWLMIHMFHCRMVLTYHMWWVCFWHWDGLVSSLYLPHLTLFLVGLAL
  LTLIINPYWTHKKTQQLLNPVDWNFAQPEAKSRPEGNGQLLRKKRP
• Function: Could play a role in cell proliferation during neuronal differentiation and in protection against cell death.

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuronal ceroid lipofuscinosis	DIS9A4K4	Definitive	Autosomal recessive	[1]
Neuronal ceroid lipofuscinosis 8	DISGNC07	Definitive	Autosomal recessive	[1]
Absence epilepsy	DISJPOUD	Strong	Biomarker	[2]
CLN2 Batten disease	DISZC5YB	Strong	Genetic Variation	[3]
Epilepsy	DISBB28L	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[4]
Late infantile neuronal ceroid lipofuscinosis	DISI3RIL	Strong	Genetic Variation	[5]
Lysosomal storage disease	DIS6QM6U	Strong	Biomarker	[3]
Neuronal ceroid lipofuscinosis 7	DISVZUFT	Strong	Genetic Variation	[6]
Neuronal ceroid lipofuscinosis 8 northern epilepsy variant	DISWF5BV	Strong	Autosomal recessive	[7]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[8]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[9]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[10]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[11]
Rheumatoid arthritis	DISTSB4J	moderate	Genetic Variation	[12]
Autism spectrum disorder	DISXK8NV	Disputed	Autosomal dominant	[13]
Adult neuronal ceroid lipofuscinosis	DIS5UHAA	Limited	Biomarker	[14]
Gaucher disease	DISTW5JG	Limited	Genetic Variation	[15]

13 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 Protein CLN8 (CLN8).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein CLN8 (CLN8).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein CLN8 (CLN8).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein CLN8 (CLN8).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein CLN8 (CLN8).	[21]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Protein CLN8 (CLN8).	[12]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Protein CLN8 (CLN8).	[23]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Protein CLN8 (CLN8).	[25]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of Protein CLN8 (CLN8).	[25]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Protein CLN8 (CLN8).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein CLN8 (CLN8).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein CLN8 (CLN8).	[28]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Protein CLN8 (CLN8).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein CLN8 (CLN8).	[20]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Protein CLN8 (CLN8).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein CLN8 (CLN8).	[24]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Protein CLN8 (CLN8).	[26]

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] Clinical and electrophysiological features of epilepsy in Italian patients with CLN8 mutations.Epilepsy Behav. 2007 Feb;10(1):187-91. doi: 10.1016/j.yebeh.2006.10.009. Epub 2006 Nov 28.
• [3] CLN8 is an endoplasmic reticulum cargo receptor that regulates lysosome biogenesis.Nat Cell Biol. 2018 Dec;20(12):1370-1377. doi: 10.1038/s41556-018-0228-7. Epub 2018 Nov 5.
• [4] Novel CLN8 mutations confirm the clinical and ethnic diversity of late infantile neuronal ceroid lipofuscinosis.Clin Genet. 2010 Jan;77(1):79-85. doi: 10.1111/j.1399-0004.2009.01285.x. Epub 2009 Oct 5.
• [5] Novel missense mutation in CLN8 in late infantile neuronal ceroid lipofuscinosis: The first report of a CLN8 mutation in Japan.Brain Dev. 2016 Mar;38(3):341-5. doi: 10.1016/j.braindev.2015.09.008. Epub 2015 Oct 9.
• [6] Turkish variant late infantile neuronal ceroid lipofuscinosis (CLN7) may be allelic to CLN8.Eur J Paediatr Neurol. 2001;5 Suppl A:21-7. doi: 10.1053/ejpn.2000.0429.
• [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] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [9] Resequencing and Association Analysis of CLN8 with Autism Spectrum Disorder in a Japanese Population.PLoS One. 2015 Dec 14;10(12):e0144624. doi: 10.1371/journal.pone.0144624. eCollection 2015.
• [10] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [11] Exome sequencing identifies a novel homozygous CLN8 mutation in a Turkish family with Northern epilepsy.Acta Neurol Belg. 2017 Mar;117(1):159-167. doi: 10.1007/s13760-016-0721-3. Epub 2016 Nov 14.
• [12] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [13] 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.
• [14] An early-onset congenic strain of the motor neuron degeneration (mnd) mouse.Mol Genet Metab. 1999 Apr;66(4):393-7. doi: 10.1006/mgme.1999.2817.
• [15] Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation.Am J Hematol. 2012 Apr;87(4):377-83. doi: 10.1002/ajh.23118. Epub 2012 Mar 3.
• [16] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [17] 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.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [21] 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.
• [22] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [23] 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.
• [24] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [25] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [26] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [27] 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.
• [28] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [29] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.