Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG4YGBR)

• DOT Name: Ceramide kinase-like protein (CERKL)
• Gene Name: CERKL
• Related Disease:
  CERKL-related retinopathy
  Inherited retinal dystrophy
  Retinitis pigmentosa 26
  Cone-rod dystrophy
  Cone-rod dystrophy 2
  Oguchi disease
  Retinopathy
  Retinitis pigmentosa
  Retinal degeneration
  Disorder of orbital region
• UniProt ID: CERKL_HUMAN
• Pfam ID: PF19280 ; PF00781
• Sequence:
  MPWRRRRNRVSALEGGREEEAPPEAAAVPPALLTSPQQTEAAAERILLRGIFEIGRDSCD
  VVLSERALRWRPIQPERPAGDSKYDLLCKEEFIELKDIFSVKLKRRCSVKQQRSGTLLGI
  TLFICLKKEQNKLKNSTLDLINLSEDHCDIWFRQFKKILAGFPNRPKSLKILLNPQSHKK
  EATQVYYEKVEPLLKLAGIKTDVTIMEYEGHALSLLKECELQGFDGGHRKPLFAIHWSVQ
  RLFTGMQTLEPSVVCVGGDGSASEVAHALLLRAQKNAGMETDRILTPVRAQLPLGLIPAG
  STNVLAHSLHGVPHVITATLHIIMGHVQLVDVCTFSTAGKLLRFGFSAMFGFGGRTLALA
  EKYRWMSPNQRRDFAVVKALAKLKAEDCEISFLPFNSSDDVQERRAQGSPKSDCNDQWQM
  IQGQFLNVSIMAIPCLCSVAPRGLAPNTRLNNGSMALIIARNTSRPEFIKHLKRYASVKN
  QFNFPFVETYTVEEVKVHPRNNTGGYNPEEEEDETASENCFPWNVDGDLMEVASEVHIRL
  HPRLISLYGGSMEEMIPK
• Function: Has no detectable ceramide-kinase activity. Overexpression of CERKL protects cells from apoptosis in oxidative stress conditions.
• Tissue Specificity: Isoform 1 and isoform 2 are expressed in adult retina, liver and pancreas as well as in fetal brain, lung and kidney. Isoform 3 is expressed in adult retina as well as in fetal lung and liver. Isoform 4 is expressed in adult retina, lung and kidney as well as in fetal lung and liver. Moderately expressed in retina, kidney, lung, testis, trachea, and pancreas. Weakly expressed in brain, placenta and liver.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
CERKL-related retinopathy	DISECNRL	Definitive	Autosomal recessive	[1]
Inherited retinal dystrophy	DISGGL77	Definitive	Genetic Variation	[2]
Retinitis pigmentosa 26	DISIAKQD	Definitive	Autosomal recessive	[3]
Cone-rod dystrophy	DISY9RWN	Strong	CausalMutation	[4]
Cone-rod dystrophy 2	DISX2RWY	Strong	Genetic Variation	[5]
Oguchi disease	DISLYKY5	Strong	Biomarker	[6]
Retinopathy	DISB4B0F	moderate	Biomarker	[7]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[8]
Retinal degeneration	DISM1JHQ	Disputed	Genetic Variation	[9]
Disorder of orbital region	DISH0ECJ	Limited	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ceramide kinase-like protein (CERKL).	[11]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Ceramide kinase-like protein (CERKL).	[13]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Ceramide kinase-like protein (CERKL).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Ceramide kinase-like protein (CERKL).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ceramide kinase-like protein (CERKL).	[14]

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] A founder mutation in CERKL is a major cause of retinal dystrophy in Finland.Acta Ophthalmol. 2018 Mar;96(2):183-191. doi: 10.1111/aos.13551. Epub 2017 Oct 25.
• [3] CERKL mutations and associated phenotypes in seven Spanish families with autosomal recessive retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2008 Jun;49(6):2709-13. doi: 10.1167/iovs.07-0865.
• [4] Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.Sci Rep. 2019 Feb 4;9(1):1219. doi: 10.1038/s41598-018-38007-2.
• [5] A case-control collapsing analysis identifies retinal dystrophy genes associated with ophthalmic disease in patients with no pathogenic ABCA4 variants.Genet Med. 2019 Oct;21(10):2336-2344. doi: 10.1038/s41436-019-0495-0. Epub 2019 Mar 30.
• [6] Phenotypic Features of Oguchi Disease and Retinitis Pigmentosa in Patients with S-Antigen Mutations: A Long-Term Follow-up Study.Ophthalmology. 2019 Nov;126(11):1557-1566. doi: 10.1016/j.ophtha.2019.05.027. Epub 2019 Jun 6.
• [7] Hyperautofluorescent Dots are Characteristic in Ceramide Kinase Like-associated Retinal Degeneration.Sci Rep. 2019 Jan 29;9(1):876. doi: 10.1038/s41598-018-37578-4.
• [8] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [9] A missense mutation in the nuclear localization signal sequence of CERKL (p.R106S) causes autosomal recessive retinal degeneration.Mol Vis. 2008;14:1960-4. Epub 2008 Oct 30.
• [10] pVHL interacts with Ceramide kinase like (CERKL) protein and ubiquitinates it for oxygen dependent proteasomal degradation.Cell Signal. 2015 Nov;27(11):2314-23. doi: 10.1016/j.cellsig.2015.08.011. Epub 2015 Aug 18.
• [11] 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.
• [12] 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.
• [13] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [14] 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.
• [15] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.