Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ9GCXL)

• DOT Name: Ribitol-5-phosphate transferase FKTN (FKTN)
• Synonyms: EC 2.7.8.-; Fukutin; Fukuyama-type congenital muscular dystrophy protein; Ribitol-5-phosphate transferase
• Gene Name: FKTN
• Related Disease:
  Autosomal recessive limb-girdle muscular dystrophy type 2M
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4
  Myopathy caused by variation in FKTN
  Advanced cancer
  Astrocytoma
  Autosomal recessive limb-girdle muscular dystrophy type 2A
  Campomelic dysplasia
  Cardiac failure
  Cardiomyopathy
  Central core myopathy
  Cobblestone lissencephaly
  Congenital fiber-type disproportion myopathy
  Congenital muscular dystrophy
  Congenital myopathy
  Congestive heart failure
  Craniometaphyseal dysplasia, autosomal dominant
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Duchenne muscular dystrophy
  Familial dilated cardiomyopathy
  Hypertrophic cardiomyopathy
  Limb-girdle muscular dystrophy
  Limb-girdle muscular dystrophy due to POMK deficiency
  Multiminicore myopathy
  Muscular dystrophy
  Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2
  Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3
  Nemaline myopathy
  Qualitative or quantitative defects of dysferlin
  Rigid spine muscular dystrophy 1
  Gastric cancer
  Intellectual disability
  Isolated congenital microcephaly
  Stomach cancer
  Muscle-eye-brain disease
  Muscular dystrophy-dystroglycanopathy, type A
  Obsolete congenital muscular dystrophy without intellectual disability
  Obsolete familial isolated dilated cardiomyopathy
  Dilated cardiomyopathy 1X
  Gallbladder cancer
  Gallbladder carcinoma
  Myopathy
• UniProt ID: FKTN_HUMAN
• EC Number: 2.7.8.-
• Pfam ID: PF19737 ; PF04991
• Sequence:
  MSRINKNVVLALLTLTSSAFLLFQLYYYKHYLSTKNGAGLSKSKGSRIGFDSTQWRAVKK
  FIMLTSNQNVPVFLIDPLILELINKNFEQVKNTSHGSTSQCKFFCVPRDFTAFALQYHLW
  KNEEGWFRIAENMGFQCLKIESKDPRLDGIDSLSGTEIPLHYICKLATHAIHLVVFHERS
  GNYLWHGHLRLKEHIDRKFVPFRKLQFGRYPGAFDRPELQQVTVDGLEVLIPKDPMHFVE
  EVPHSRFIECRYKEARAFFQQYLDDNTVEAVAFRKSAKELLQLAAKTLNKLGVPFWLSSG
  TCLGWYRQCNIIPYSKDVDLGIFIQDYKSDIILAFQDAGLPLKHKFGKVEDSLELSFQGK
  DDVKLDVFFFYEETDHMWNGGTQAKTGKKFKYLFPKFTLCWTEFVDMKVHVPCETLEYIE
  ANYGKTWKIPVKTWDWKRSPPNVQPNGIWPISEWDEVIQLY
• Function: Catalyzes the transfer of a ribitol-phosphate from CDP-ribitol to the distal N-acetylgalactosamine of 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 first step in the formation of the ribitol 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. Required for normal location of POMGNT1 in Golgi membranes, and for normal POMGNT1 activity. May interact with and reinforce a large complex encompassing the outside and inside of muscle membranes. Could be involved in brain development (Probable).
• Tissue Specificity: Expressed in the retina (at protein level) . Widely expressed with highest expression in brain, heart, pancreas and skeletal muscle . Expressed at similar levels in control fetal and adult brain . Expressed in migrating neurons, including Cajar-Retzius cells and adult cortical neurons, as well as hippocampal pyramidal cells and cerebellar Purkinje cells . No expression observed in the glia limitans, the subpial astrocytes (which contribute to basement membrane formation) or other glial cells .
• KEGG Pathway:
  Mannose type O-glycan biosynthesis (hsa00515)
  Metabolic pathways (hsa01100)
• BioCyc Pathway: MetaCyc:ENSG00000106692-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive limb-girdle muscular dystrophy type 2M	DISZUNT4	Definitive	Autosomal recessive	[1]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	DISGM0K5	Definitive	Autosomal recessive	[2]
Myopathy caused by variation in FKTN	DISXRJUG	Definitive	Autosomal recessive	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Astrocytoma	DISL3V18	Strong	Altered Expression	[5]
Autosomal recessive limb-girdle muscular dystrophy type 2A	DISIHX4S	Strong	Biomarker	[6]
Campomelic dysplasia	DISVTW53	Strong	Genetic Variation	[7]
Cardiac failure	DISDC067	Strong	Biomarker	[8]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[8]
Central core myopathy	DIS18AZZ	Strong	Biomarker	[9]
Cobblestone lissencephaly	DIS56826	Strong	Genetic Variation	[10]
Congenital fiber-type disproportion myopathy	DISU9T2M	Strong	Biomarker	[9]
Congenital muscular dystrophy	DISKY7OY	Strong	Genetic Variation	[10]
Congenital myopathy	DISLSK9G	Strong	Biomarker	[9]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[8]
Craniometaphyseal dysplasia, autosomal dominant	DISU12OO	Strong	Genetic Variation	[7]
Dilated cardiomyopathy	DISX608J	Strong	Genetic Variation	[11]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[11]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Genetic Variation	[12]
Familial dilated cardiomyopathy	DISBHDU9	Strong	GermlineCausalMutation	[13]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[11]
Limb-girdle muscular dystrophy	DISI9Y1Z	Strong	Genetic Variation	[14]
Limb-girdle muscular dystrophy due to POMK deficiency	DISM63SY	Strong	Biomarker	[9]
Multiminicore myopathy	DISE6VYN	Strong	Biomarker	[9]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[15]
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2	DIS2BGID	Strong	Biomarker	[9]
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	DISSP7OL	Strong	Biomarker	[9]
Nemaline myopathy	DIS5IYLY	Strong	Biomarker	[9]
Qualitative or quantitative defects of dysferlin	DIS59VEJ	Strong	Biomarker	[6]
Rigid spine muscular dystrophy 1	DISHZE8T	Strong	Biomarker	[14]
Gastric cancer	DISXGOUK	moderate	Biomarker	[16]
Intellectual disability	DISMBNXP	moderate	Biomarker	[14]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[17]
Stomach cancer	DISKIJSX	moderate	Biomarker	[16]
Muscle-eye-brain disease	DISJUOQB	Supportive	Autosomal recessive	[18]
Muscular dystrophy-dystroglycanopathy, type A	DISZTBC4	Supportive	Autosomal recessive	[19]
Obsolete congenital muscular dystrophy without intellectual disability	DISGKCTZ	Supportive	Autosomal recessive	[20]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[13]
Dilated cardiomyopathy 1X	DISXZPMT	Limited	Autosomal recessive	[21]
Gallbladder cancer	DISXJUAF	Limited	Biomarker	[22]
Gallbladder carcinoma	DISD6ACL	Limited	Biomarker	[22]
Myopathy	DISOWG27	Limited	Biomarker	[23]

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 Ribitol-5-phosphate transferase FKTN (FKTN).	[24]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ribitol-5-phosphate transferase FKTN (FKTN).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ribitol-5-phosphate transferase FKTN (FKTN).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ribitol-5-phosphate transferase FKTN (FKTN).	[27]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ribitol-5-phosphate transferase FKTN (FKTN).	[28]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Ribitol-5-phosphate transferase FKTN (FKTN).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ribitol-5-phosphate transferase FKTN (FKTN).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ribitol-5-phosphate transferase FKTN (FKTN).	[31]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Ribitol-5-phosphate transferase FKTN (FKTN).	[32]

References

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• [2] A new mutation of the fukutin gene in a non-Japanese patient. Ann Neurol. 2003 Mar;53(3):392-6. doi: 10.1002/ana.10491.
• [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] A role of fukutin, a gene responsible for Fukuyama type congenital muscular dystrophy, in cancer cells: a possible role to suppress cell proliferation.Int J Exp Pathol. 2008 Oct;89(5):332-41. doi: 10.1111/j.1365-2613.2008.00599.x.
• [5] Post-transcriptional regulation of fukutin in an astrocytoma cell line.Int J Exp Pathol. 2012 Feb;93(1):46-55. doi: 10.1111/j.1365-2613.2011.00799.x.
• [6] Common recessive limb girdle muscular dystrophies differential diagnosis: why and how?.Arq Neuropsiquiatr. 2014 Sep;72(9):721-34. doi: 10.1590/0004-282x20140110.
• [7] A variant of congenital muscular dystrophy.Brain Dev. 2002 Jan;24(1):24-9. doi: 10.1016/s0387-7604(01)00384-9.
• [8] Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure.Nat Commun. 2019 Dec 17;10(1):5754. doi: 10.1038/s41467-019-13623-2.
• [9] Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy.Hum Mol Genet. 2009 Feb 15;18(4):621-31. doi: 10.1093/hmg/ddn387. Epub 2008 Nov 18.
• [10] Fukutin mutations in non-Japanese patients with congenital muscular dystrophy: less severe mutations predominate in patients with a non-Walker-Warburg phenotype.Neuromuscul Disord. 2011 Jan;21(1):20-30. doi: 10.1016/j.nmd.2010.08.007. Epub 2010 Oct 18.
• [11] Mutational analysis of fukutin gene in dilated cardiomyopathy and hypertrophic cardiomyopathy.Circ J. 2009 Jan;73(1):158-61. doi: 10.1253/circj.cj-08-0722. Epub 2008 Nov 17.
• [12] Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy.Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):623-7. doi: 10.1073/pnas.89.2.623.
• [13] Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness. Ann Neurol. 2006 Nov;60(5):597-602. doi: 10.1002/ana.20973.
• [14] A new mutation of the fukutin gene causing late-onset limb girdle muscular dystrophy.Neuromuscul Disord. 2013 Jul;23(7):562-7. doi: 10.1016/j.nmd.2013.04.006. Epub 2013 Jun 6.
• [15] National registry of patients with Fukuyama congenital muscular dystrophy in Japan.Neuromuscul Disord. 2018 Oct;28(10):885-893. doi: 10.1016/j.nmd.2018.08.001. Epub 2018 Aug 10.
• [16] Characteristic expression of fukutin in gastric cancer among atomic bomb survivors.Oncol Lett. 2017 Feb;13(2):937-941. doi: 10.3892/ol.2016.5520. Epub 2016 Dec 20.
• [17] Novel mutation in the fukutin gene in an Egyptian family with Fukuyama congenital muscular dystrophy and microcephaly.Gene. 2014 Apr 15;539(2):279-82. doi: 10.1016/j.gene.2014.01.070. Epub 2014 Feb 13.
• [18] Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain. 2007 Oct;130(Pt 10):2725-35. doi: 10.1093/brain/awm212. Epub 2007 Sep 18.
• [19] Two new patients bearing mutations in the fukutin gene confirm the relevance of this gene in Walker-Warburg syndrome. Clin Genet. 2008 Feb;73(2):139-45. doi: 10.1111/j.1399-0004.2007.00936.x. Epub 2007 Dec 19.
• [20] 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.
• [21] 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.
• [22] Sequential occurrence of preneoplastic lesions and accumulation of loss of heterozygosity in patients with gallbladder stones suggest causal association with gallbladder cancer.Ann Surg. 2014 Dec;260(6):1073-80. doi: 10.1097/SLA.0000000000000495.
• [23] 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.
• [24] 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.
• [25] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [26] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [27] 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.
• [28] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [29] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [30] 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.
• [31] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [32] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.