Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ0CCJ8)

• DOT Name: Mannose-1-phosphate guanyltransferase beta (GMPPB)
• Synonyms: EC 2.7.7.13; GDP-mannose pyrophosphorylase B; GTP-mannose-1-phosphate guanylyltransferase beta
• Gene Name: GMPPB
• Related Disease:
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14
  Myopathy caused by variation in GMPPB
  Autosomal recessive limb-girdle muscular dystrophy type 2T
  Centronuclear myopathy
  Congenital myasthenic syndrome
  LambertEaton myasthenic syndrome
  Muscular dystrophy
  Limb-girdle muscular dystrophy
  Congenital muscular dystrophy with intellectual disability
  Muscle-eye-brain disease
  Obsolete congenital muscular dystrophy with cerebellar involvement
  Obsolete congenital myasthenic syndromes with glycosylation defect
  Intellectual disability
  Metabolic myopathy
• UniProt ID: GMPPB_HUMAN
• PDB ID: 7D72; 7D73; 7D74
• EC Number: 2.7.7.13
• Pfam ID: PF00132 ; PF00483
• Sequence:
  MKALILVGGYGTRLRPLTLSTPKPLVDFCNKPILLHQVEALAAAGVDHVILAVSYMSQVL
  EKEMKAQEQRLGIRISMSHEEEPLGTAGPLALARDLLSETADPFFVLNSDVICDFPFQAM
  VQFHRHHGQEGSILVTKVEEPSKYGVVVCEADTGRIHRFVEKPQVFVSNKINAGMYILSP
  AVLQRIQLQPTSIEKEVFPIMAKEGQLYAMELQGFWMDIGQPKDFLTGMCLFLQSLRQKQ
  PERLCSGPGIVGNVLVDPSARIGQNCSIGPNVSLGPGVVVEDGVCIRRCTVLRDARIRSH
  SWLESCIVGWRCRVGQWVRMENVTVLGEDVIVNDELYLNGASVLPHKSIGESVPEPRIIM
• Function: Catalyzes the formation of GDP-mannose, an essential precursor of glycan moieties of glycoproteins and glycolipids.
• KEGG Pathway:
  Fructose and mannose metabolism (hsa00051)
  Amino sugar and nucleotide sugar metabolism (hsa00520)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  Biosynthesis of nucleotide sugars (hsa01250)
• Reactome Pathway: Synthesis of GDP-mannose (R-HSA-446205)

Molecular Interaction Atlas (MIA) of This DOT

14 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 A14	DISD5A6W	Definitive	Autosomal recessive	[1]
Myopathy caused by variation in GMPPB	DIS42PW9	Definitive	Autosomal recessive	[2]
Autosomal recessive limb-girdle muscular dystrophy type 2T	DISYWUPW	Strong	Autosomal recessive	[3]
Centronuclear myopathy	DISXBEJO	Strong	Genetic Variation	[4]
Congenital myasthenic syndrome	DISJLG2T	Strong	Autosomal recessive	[5]
LambertEaton myasthenic syndrome	DISN0Q7Q	Strong	Genetic Variation	[6]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[4]
Limb-girdle muscular dystrophy	DISI9Y1Z	moderate	Genetic Variation	[6]
Congenital muscular dystrophy with intellectual disability	DISWHF75	Supportive	Autosomal recessive	[1]
Muscle-eye-brain disease	DISJUOQB	Supportive	Autosomal recessive	[1]
Obsolete congenital muscular dystrophy with cerebellar involvement	DIS8CGS1	Supportive	Autosomal recessive	[1]
Obsolete congenital myasthenic syndromes with glycosylation defect	DISIGACA	Supportive	Autosomal recessive	[7]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[8]
Metabolic myopathy	DISSE3BW	Limited	Biomarker	[9]

9 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 Mannose-1-phosphate guanyltransferase beta (GMPPB).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mannose-1-phosphate guanyltransferase beta (GMPPB).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mannose-1-phosphate guanyltransferase beta (GMPPB).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mannose-1-phosphate guanyltransferase beta (GMPPB).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Mannose-1-phosphate guanyltransferase beta (GMPPB).	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Mannose-1-phosphate guanyltransferase beta (GMPPB).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Mannose-1-phosphate guanyltransferase beta (GMPPB).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mannose-1-phosphate guanyltransferase beta (GMPPB).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mannose-1-phosphate guanyltransferase beta (GMPPB).	[18]

References

• [1] Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of -dystroglycan. Am J Hum Genet. 2013 Jul 11;93(1):29-41. doi: 10.1016/j.ajhg.2013.05.009. Epub 2013 Jun 13.
• [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] PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet. 2019 Nov;51(11):1560-1565. doi: 10.1038/s41588-019-0528-2.
• [4] A homozygous mutation in GMPPB leads to centronuclear myopathy with combined pre- and postsynaptic defects of neuromuscular transmission.Neuromuscul Disord. 2019 Aug;29(8):614-617. doi: 10.1016/j.nmd.2019.07.001. Epub 2019 Jul 5.
• [5] 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.
• [6] Novel mutations in the C-terminal region of GMPPB causing limb-girdle muscular dystrophy overlapping with congenital myasthenic syndrome.Neuromuscul Disord. 2017 Jun;27(6):557-564. doi: 10.1016/j.nmd.2017.03.004. Epub 2017 Mar 10.
• [7] Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies. Brain. 2015 Sep;138(Pt 9):2493-504. doi: 10.1093/brain/awv185. Epub 2015 Jun 30.
• [8] Late-onset limb-girdle muscular dystrophy caused by GMPPB mutations.Neuromuscul Disord. 2017 Jul;27(7):627-630. doi: 10.1016/j.nmd.2017.04.006. Epub 2017 Apr 18.
• [9] Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study.Orphanet J Rare Dis. 2018 Sep 26;13(1):170. doi: 10.1186/s13023-018-0863-x.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [14] 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.
• [15] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [16] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [17] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.