Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC85K8Q)

• DOT Name: D-ribitol-5-phosphate cytidylyltransferase (CRPPA)
• Synonyms: EC 2.7.7.40; 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase-like protein; Isoprenoid synthase domain-containing protein; hISPD
• Gene Name: CRPPA
• Related Disease:
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7
  Myopathy caused by variation in CRPPA
  Anemia
  Clear cell renal carcinoma
  Congenital muscular dystrophy
  Hydrocephalus
  Limb-girdle muscular dystrophy
  Muscular dystrophy
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1
  Neural tube defect
  Cobblestone lissencephaly
  Myopathy
  Autosomal recessive limb-girdle muscular dystrophy type 2U
  Muscular dystrophy-dystroglycanopathy, type A
  Obsolete congenital muscular dystrophy without intellectual disability
  Autosomal recessive limb-girdle muscular dystrophy type 2K
  Communicating hydrocephalus
  Congenital hydrocephalus
  Muscle-eye-brain disease
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4
  Pneumonia
• UniProt ID: ISPD_HUMAN
• PDB ID: 4CVH
• EC Number: 2.7.7.40
• Pfam ID: PF01128 ; PF18706
• Sequence:
  MEAGPPGSARPAEPGPCLSGQRGADHTASASLQSVAGTEPGRHPQAVAAVLPAGGCGERM
  GVPTPKQFCPILERPLISYTLQALERVCWIKDIVVAVTGENMEVMKSIIQKYQHKRISLV
  EAGVTRHRSIFNGLKALAEDQINSKLSKPEVVIIHDAVRPFVEEGVLLKVVTAAKEHGAA
  GAIRPLVSTVVSPSADGCLDYSLERARHRASEMPQAFLFDVIYEAYQQCSDYDLEFGTEC
  LQLALKYCCTKAKLVEGSPDLWKVTYKRDLYAAESIIKERISQEICVVMDTEEDNKHVGH
  LLEEVLKSELNHVKVTSEALGHAGRHLQQIILDQCYNFVCVNVTTSDFQETQKLLSMLEE
  SSLCILYPVVVVSVHFLDFKLVPPSQKMENLMQIREFAKEVKERNILLYGLLISYPQDDQ
  KLQESLRQGAIIIASLIKERNSGLIGQLLIA
• Function: Cytidylyltransferase required for protein O-linked mannosylation. Catalyzes the formation of CDP-ribitol nucleotide sugar from D-ribitol 5-phosphate. CDP-ribitol is a substrate of FKTN during the biosynthesis 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), which is required for binding laminin G-like domain-containing extracellular proteins with high affinity. Shows activity toward other pentose phosphate sugars and mediates formation of CDP-ribulose or CDP-ribose using CTP and ribulose-5-phosphate or ribose-5-phosphate, respectively. Not Involved in dolichol production.
• Tissue Specificity: Ubiquitously expressed, with high expression in brain.
• KEGG Pathway:
  Pentose and glucuro.te interconversions (hsa00040)
  Mannose type O-glycan biosynthesis (hsa00515)
  Metabolic pathways (hsa01100)
• BioCyc Pathway: MetaCyc:MONOMER66-43822

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7	DISP2UZU	Definitive	Autosomal recessive	[1]
Myopathy caused by variation in CRPPA	DISX6ABY	Definitive	Autosomal recessive	[2]
Anemia	DISTVL0C	Strong	Genetic Variation	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[4]
Congenital muscular dystrophy	DISKY7OY	Strong	Biomarker	[5]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[6]
Limb-girdle muscular dystrophy	DISI9Y1Z	Strong	Biomarker	[7]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[8]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1	DISQLATN	Strong	Biomarker	[9]
Neural tube defect	DIS5J95E	Strong	Genetic Variation	[10]
Cobblestone lissencephaly	DIS56826	moderate	Genetic Variation	[10]
Myopathy	DISOWG27	moderate	Biomarker	[11]
Autosomal recessive limb-girdle muscular dystrophy type 2U	DIS63XZV	Supportive	Autosomal recessive	[5]
Muscular dystrophy-dystroglycanopathy, type A	DISZTBC4	Supportive	Autosomal recessive	[9]
Obsolete congenital muscular dystrophy without intellectual disability	DISGKCTZ	Supportive	Autosomal recessive	[5]
Autosomal recessive limb-girdle muscular dystrophy type 2K	DIS0FJ08	Limited	Biomarker	[6]
Communicating hydrocephalus	DIS33112	Limited	Biomarker	[6]
Congenital hydrocephalus	DIS7O6UL	Limited	Biomarker	[6]
Muscle-eye-brain disease	DISJUOQB	Limited	Biomarker	[6]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	DISGM0K5	Limited	Biomarker	[6]
Pneumonia	DIS8EF3M	Limited	Biomarker	[12]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cycloheximide	DMGDA3C	Investigative	D-ribitol-5-phosphate cytidylyltransferase (CRPPA) affects the response to substance of Cycloheximide.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of D-ribitol-5-phosphate cytidylyltransferase (CRPPA).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of D-ribitol-5-phosphate cytidylyltransferase (CRPPA).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of D-ribitol-5-phosphate cytidylyltransferase (CRPPA).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of D-ribitol-5-phosphate cytidylyltransferase (CRPPA).	[16]

References

• [1] Walker-Warburg syndrome: neurologic features and muscle membrane structure. Pediatr Neurol. 1998 Jan;18(1):76-80. doi: 10.1016/s0887-8994(97)00137-9.
• [2] 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.
• [3] Efficacy and safety of Everolimus and Exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2-) advanced breast cancer patients: New insights beyond clinical trials. The EVA study.Breast. 2017 Oct;35:115-121. doi: 10.1016/j.breast.2017.06.043. Epub 2017 Jul 13.
• [4] Downregulation of dystroglycan glycosyltransferases LARGE2 and ISPD associate with increased mortality in clear cell renal cell carcinoma.Mol Cancer. 2015 Jul 30;14:141. doi: 10.1186/s12943-015-0416-z.
• [5] ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies. Brain. 2013 Jan;136(Pt 1):269-81. doi: 10.1093/brain/aws312. Epub 2013 Jan 3.
• [6] Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of -dystroglycan.Nat Genet. 2012 May;44(5):581-5. doi: 10.1038/ng.2253.
• [7] Impact of next-generation sequencing panels in the evaluation of limb-girdle muscular dystrophies.Ann Hum Genet. 2019 Sep;83(5):331-347. doi: 10.1111/ahg.12319. Epub 2019 May 7.
• [8] 160 kb deletion in ISPD unmasking a recessive mutation in a patient with Walker-Warburg syndrome.Eur J Med Genet. 2013 Dec;56(12):689-94. doi: 10.1016/j.ejmg.2013.09.014. Epub 2013 Oct 10.
• [9] ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome. Nat Genet. 2012 May;44(5):575-80. doi: 10.1038/ng.2252.
• [10] Identification of mutations in TMEM5 and ISPD as a cause of severe cobblestone lissencephaly. Am J Hum Genet. 2012 Dec 7;91(6):1135-43. doi: 10.1016/j.ajhg.2012.10.009.
• [11] 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.
• [12] Indirect (herd) protection, following pneumococcal conjugated vaccines introduction: A systematic review of the literature.Vaccine. 2017 May 19;35(22):2882-2891. doi: 10.1016/j.vaccine.2017.04.032. Epub 2017 Apr 24.
• [13] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [15] 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.
• [16] 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.
• [17] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.