Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMUZ7GH)

• DOT Name: Ribitol 5-phosphate transferase FKRP (FKRP)
• Synonyms: EC 2.7.8.-; Fukutin-related protein; Ribitol-5-phosphate transferase
• Gene Name: FKRP
• Related Disease:
  Autosomal recessive limb-girdle muscular dystrophy type 2I
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
  Muscular dystrophy-dystroglycanopathy type B5
  Myopathy caused by variation in FKRP
  Autosomal recessive limb-girdle muscular dystrophy type 2A
  Becker muscular dystrophy
  Bethlem myopathy
  Campomelic dysplasia
  Cardiac failure
  Cardiomyopathy
  Central core myopathy
  Cobblestone lissencephaly
  Congenital fiber-type disproportion myopathy
  Congenital muscular dystrophy
  Congenital myopathy
  Congenital nervous system disorder
  Congestive heart failure
  Craniometaphyseal dysplasia, autosomal dominant
  Dilated cardiomyopathy 1A
  Intellectual disability
  Limb-girdle muscular dystrophy
  Limb-girdle muscular dystrophy due to POMK deficiency
  Multiminicore myopathy
  Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2
  Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3
  Myopathy
  Myositis disease
  Nasopharyngeal carcinoma
  Nemaline myopathy
  Neuromuscular disease
  Type-1 diabetes
  Ventricular tachycardia
  Autosomal recessive limb-girdle muscular dystrophy type 2D
  Autosomal recessive limb-girdle muscular dystrophy type 2H
  Congenital muscular dystrophy with intellectual disability
  Muscle-eye-brain disease
  Muscular dystrophy-dystroglycanopathy, type A
  Obsolete congenital muscular dystrophy with cerebellar involvement
  Obsolete congenital muscular dystrophy without intellectual disability
  Small lymphocytic lymphoma
  Dilated cardiomyopathy
  Muscular dystrophy
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4
• UniProt ID: FKRP_HUMAN
• PDB ID: 6KAJ; 6KAK; 6KAL; 6KAM; 6KAN; 6L7S; 6L7T; 6L7U
• EC Number: 2.7.8.-
• Pfam ID: PF04991
• Sequence:
  MRLTRCQAALAAAITLNLLVLFYVSWLQHQPRNSRARGPRRASAAGPRVTVLVREFEAFD
  NAVPELVDSFLQQDPAQPVVVAADTLPYPPLALPRIPNVRLALLQPALDRPAAASRPETY
  VATEFVALVPDGARAEAPGLLERMVEALRAGSARLVAAPVATANPARCLALNVSLREWTA
  RYGAAPAAPRCDALDGDAVVLLRARDLFNLSAPLARPVGTSLFLQTALRGWAVQLLDLTF
  AAARQPPLATAHARWKAEREGRARRAALLRALGIRLVSWEGGRLEWFGCNKETTRCFGTV
  VGDTPAYLYEERWTPPCCLRALRETARYVVGVLEAAGVRYWLEGGSLLGAARHGDIIPWD
  YDVDLGIYLEDVGNCEQLRGAEAGSVVDERGFVWEKAVEGDFFRVQYSESNHLHVDLWPF
  YPRNGVMTKDTWLDHRQDVEFPEHFLQPLVPLPFAGFVAQAPNNYRRFLELKFGPGVIEN
  PQYPNPALLSLTGSG
• Function: Catalyzes the transfer of a ribitol 5-phosphate from CDP-L-ribitol to the ribitol 5-phosphate previously attached by FKTN/fukutin to the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-3-N-acetylglucosamine-beta-4-(phosphate-6-)mannose), a carbohydrate structure present in alpha-dystroglycan (DAG1). This constitutes the second step in the formation of the ribose 5-phosphate tandem repeat which links the phosphorylated O-mannosyl trisaccharide to the ligand binding moiety composed of repeats of 3-xylosyl-alpha-1,3-glucuronic acid-beta-1.
• Tissue Specificity: Expressed in the retina (at protein level) . Expressed predominantly in skeletal muscle, placenta, and heart and relatively weakly in brain, lung, liver, kidney, and pancreas .
• KEGG Pathway:
  Mannose type O-glycan biosynthesis (hsa00515)
  Metabolic pathways (hsa01100)
• BioCyc Pathway: MetaCyc:ENSG00000181027-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive limb-girdle muscular dystrophy type 2I	DISINP9B	Definitive	Autosomal recessive	[1]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5	DISLXI1U	Definitive	Autosomal recessive	[2]
Muscular dystrophy-dystroglycanopathy type B5	DISH7DO5	Definitive	Autosomal recessive	[3]
Myopathy caused by variation in FKRP	DISZKUF8	Definitive	Autosomal recessive	[3]
Autosomal recessive limb-girdle muscular dystrophy type 2A	DISIHX4S	Strong	Biomarker	[4]
Becker muscular dystrophy	DIS5IYHL	Strong	Biomarker	[5]
Bethlem myopathy	DISVF5K2	Strong	Biomarker	[6]
Campomelic dysplasia	DISVTW53	Strong	Genetic Variation	[7]
Cardiac failure	DISDC067	Strong	Genetic Variation	[8]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[9]
Central core myopathy	DIS18AZZ	Strong	Biomarker	[10]
Cobblestone lissencephaly	DIS56826	Strong	Genetic Variation	[11]
Congenital fiber-type disproportion myopathy	DISU9T2M	Strong	Biomarker	[10]
Congenital muscular dystrophy	DISKY7OY	Strong	Genetic Variation	[12]
Congenital myopathy	DISLSK9G	Strong	Biomarker	[10]
Congenital nervous system disorder	DIS2BIP8	Strong	Genetic Variation	[13]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[8]
Craniometaphyseal dysplasia, autosomal dominant	DISU12OO	Strong	Genetic Variation	[7]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[14]
Intellectual disability	DISMBNXP	Strong	Biomarker	[15]
Limb-girdle muscular dystrophy	DISI9Y1Z	Strong	Genetic Variation	[16]
Limb-girdle muscular dystrophy due to POMK deficiency	DISM63SY	Strong	Biomarker	[10]
Multiminicore myopathy	DISE6VYN	Strong	Biomarker	[10]
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2	DIS2BGID	Strong	Biomarker	[10]
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	DISSP7OL	Strong	Biomarker	[10]
Myopathy	DISOWG27	Strong	Biomarker	[17]
Myositis disease	DISCIXF0	Strong	Genetic Variation	[18]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[19]
Nemaline myopathy	DIS5IYLY	Strong	Biomarker	[10]
Neuromuscular disease	DISQTIJZ	Strong	Genetic Variation	[4]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[20]
Ventricular tachycardia	DISIBXJ3	Strong	Biomarker	[14]
Autosomal recessive limb-girdle muscular dystrophy type 2D	DISRD6EW	moderate	Biomarker	[21]
Autosomal recessive limb-girdle muscular dystrophy type 2H	DISZ100M	moderate	Genetic Variation	[22]
Congenital muscular dystrophy with intellectual disability	DISWHF75	Supportive	Autosomal recessive	[23]
Muscle-eye-brain disease	DISJUOQB	Supportive	Autosomal recessive	[24]
Muscular dystrophy-dystroglycanopathy, type A	DISZTBC4	Supportive	Autosomal recessive	[25]
Obsolete congenital muscular dystrophy with cerebellar involvement	DIS8CGS1	Supportive	Autosomal recessive	[23]
Obsolete congenital muscular dystrophy without intellectual disability	DISGKCTZ	Supportive	Autosomal recessive	[23]
Small lymphocytic lymphoma	DIS30POX	Disputed	Genetic Variation	[26]
Dilated cardiomyopathy	DISX608J	Limited	Genetic Variation	[27]
Muscular dystrophy	DISJD6P7	Limited	Biomarker	[12]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	DISGM0K5	Limited	Genetic Variation	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ribitol 5-phosphate transferase FKRP (FKRP).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ribitol 5-phosphate transferase FKRP (FKRP).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ribitol 5-phosphate transferase FKRP (FKRP).	[30]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ribitol 5-phosphate transferase FKRP (FKRP).	[31]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ribitol 5-phosphate transferase FKRP (FKRP).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ribitol 5-phosphate transferase FKRP (FKRP).	[33]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ribitol 5-phosphate transferase FKRP (FKRP).	[34]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ribitol 5-phosphate transferase FKRP (FKRP).	[36]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Ribitol 5-phosphate transferase FKRP (FKRP).	[37]

References

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• [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] Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic.BMC Neurol. 2014 Aug 19;14:154. doi: 10.1186/s12883-014-0154-7.
• [5] Calpain 3 is important for muscle regeneration: evidence from patients with limb girdle muscular dystrophies.BMC Musculoskelet Disord. 2012 Mar 23;13:43. doi: 10.1186/1471-2474-13-43.
• [6] Reliability and accuracy of skeletal muscle imaging in limb-girdle muscular dystrophies.Neurology. 2012 Oct 16;79(16):1716-23. doi: 10.1212/WNL.0b013e31826e9b73. Epub 2012 Oct 3.
• [7] Overexpression of Mutant FKRP Restores Functional Glycosylation and Improves Dystrophic Phenotype in FKRP Mutant Mice.Mol Ther Nucleic Acids. 2018 Jun 1;11:216-227. doi: 10.1016/j.omtn.2018.02.008. Epub 2018 Mar 6.
• [8] The phenotype of limb-girdle muscular dystrophy type 2I.Neurology. 2003 Apr 22;60(8):1246-51. doi: 10.1212/01.wnl.0000058902.88181.3d.
• [9] Muscle and heart function restoration in a limb girdle muscular dystrophy 2I (LGMD2I) mouse model by systemic FKRP gene delivery.Mol Ther. 2014 Nov;22(11):1890-9. doi: 10.1038/mt.2014.141. Epub 2014 Jul 22.
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• [11] Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies.Brain. 2012 Feb;135(Pt 2):469-82. doi: 10.1093/brain/awr357. Epub 2012 Feb 9.
• [12] Skeletal, cardiac, and respiratory muscle function and histopathology in the P448Lneo- mouse model of FKRP-deficient muscular dystrophy.Skelet Muscle. 2018 Apr 6;8(1):13. doi: 10.1186/s13395-018-0158-x.
• [13] New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families.Neurogenetics. 2004 Feb;5(1):27-34. doi: 10.1007/s10048-003-0165-9. Epub 2003 Dec 2.
• [14] Ion Channel Dysfunctions in Dilated Cardiomyopathy in Limb-Girdle Muscular Dystrophy.Circ Genom Precis Med. 2018 Mar;11(3):e001893. doi: 10.1161/CIRCGEN.117.001893.
• [15] Fukutin-related protein mutations that cause congenital muscular dystrophy result in ER-retention of the mutant protein in cultured cells.Hum Mol Genet. 2005 Jan 15;14(2):295-305. doi: 10.1093/hmg/ddi026. Epub 2004 Dec 1.
• [16] Demembranated skeletal and cardiac fibers produce less force with altered cross-bridge kinetics in a mouse model for limb-girdle muscular dystrophy 2i.Am J Physiol Cell Physiol. 2019 Aug 1;317(2):C226-C234. doi: 10.1152/ajpcell.00524.2018. Epub 2019 May 15.
• [17] Cytidine Diphosphate-Ribitol Analysis for Diagnostics and Treatment Monitoring of Cytidine Diphosphate-l-Ribitol Pyrophosphorylase A Muscular Dystrophy.Clin Chem. 2019 Oct;65(10):1295-1306. doi: 10.1373/clinchem.2019.305391. Epub 2019 Aug 2.
• [18] Congenital muscular dystrophy with muscle inflammation alpha dystroglycan glycosylation defect and no mutation in FKRP gene.J Neurol Sci. 2006 Apr 15;243(1-2):47-51. doi: 10.1016/j.jns.2005.11.024. Epub 2006 Jan 4.
• [19] A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet. 2010 Jul;42(7):599-603. doi: 10.1038/ng.601. Epub 2010 May 30.
• [20] A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci.PLoS Genet. 2011 Sep;7(9):e1002293. doi: 10.1371/journal.pgen.1002293. Epub 2011 Sep 29.
• [21] Diagnostic value of muscle MRI in differentiating LGMD2I from other LGMDs.J Neurol. 2005 May;252(5):538-47. doi: 10.1007/s00415-005-0684-4. Epub 2005 Feb 23.
• [22] Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients.Clin Genet. 2019 Aug;96(2):126-133. doi: 10.1111/cge.13544. Epub 2019 May 6.
• [23] Dystroglycanopathies: coming into focus. Curr Opin Genet Dev. 2011 Jun;21(3):278-85. doi: 10.1016/j.gde.2011.02.001. Epub 2011 Mar 11.
• [24] Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome. J Med Genet. 2004 May;41(5):e61. doi: 10.1136/jmg.2003.013870.
• [25] A homozygous FKRP start codon mutation is associated with Walker-Warburg syndrome, the severe end of the clinical spectrum. Clin Genet. 2010 Sep;78(3):275-81. doi: 10.1111/j.1399-0004.2010.01384.x. Epub 2010 Feb 11.
• [26] Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk.Nat Genet. 2010 Feb;42(2):132-6. doi: 10.1038/ng.510. Epub 2010 Jan 10.
• [27] Heart transplantation in a child with LGMD2I presenting as isolated dilated cardiomyopathy.Neuromuscul Disord. 2008 Feb;18(2):153-5. doi: 10.1016/j.nmd.2007.09.013. Epub 2007 Dec 3.
• [28] Novel FKRP mutations in a Japanese MDC1C sibship clinically diagnosed with Fukuyama congenital muscular dystrophy.Brain Dev. 2017 Nov;39(10):869-872. doi: 10.1016/j.braindev.2017.05.013. Epub 2017 Jun 17.
• [29] 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.
• [30] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [31] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [32] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [33] 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.
• [34] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [35] 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.
• [36] 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.
• [37] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.