Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGQSHL5)

• DOT Name: Protein O-mannosyl-transferase 1 (POMT1)
• Synonyms: EC 2.4.1.109; Dolichyl-phosphate-mannose--protein mannosyltransferase 1
• Gene Name: POMT1
• Related Disease:
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1
  Myopathy caused by variation in POMT1
  Autosomal recessive limb-girdle muscular dystrophy type 2A
  Brain disease
  Brain neoplasm
  Campomelic dysplasia
  Cleft lip/palate
  Cobblestone lissencephaly
  Craniometaphyseal dysplasia, autosomal dominant
  Hydrocephalus
  Limb-girdle muscular dystrophy
  Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1
  Congenital muscular dystrophy
  Intellectual disability
  Muscular dystrophy
  Neuromuscular disease
  Autosomal recessive limb-girdle muscular dystrophy type 2K
  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
  Cardiomyopathy
  Isolated congenital microcephaly
• UniProt ID: POMT1_HUMAN
• EC Number: 2.4.1.109
• Pfam ID: PF02815 ; PF02366 ; PF16192
• Sequence:
  MWGFLKRPVVVTADINLSLVALTGMGLLSRLWRLTYPRAVVFDEVYYGQYISFYMKQIFF
  LDDSGPPFGHMVLALGGYLGGFDGNFLWNRIGAEYSSNVPVWSLRLLPALAGALSVPMAY
  QIVLELHFSHCAAMGAALLMLIENALITQSRLMLLESVLIFFNLLAVLSYLKFFNCQKHS
  PFSLSWWFWLTLTGVACSCAVGIKYMGVFTYVLVLGVAAVHAWHLLGDQTLSNVGADVQC
  CMRPACMGQMQMSQGVCVFCHLLARAVALLVIPVVLYLLFFYVHLILVFRSGPHDQIMSS
  AFQASLEGGLARITQGQPLEVAFGSQVTLRNVFGKPVPCWLHSHQDTYPMIYENGRGSSH
  QQQVTCYPFKDVNNWWIVKDPRRHQLVVSSPPRPVRHGDMVQLVHGMTTRSLNTHDVAAP
  LSPHSQEVSCYIDYNISMPAQNLWRLEIVNRGSDTDVWKTILSEVRFVHVNTSAVLKLSG
  AHLPDWGYRQLEIVGEKLSRGYHGSTVWNVEEHRYGASQEQRERERELHSPAQVDVSRNL
  SFMARFSELQWRMLALRSDDSEHKYSSSPLEWVTLDTNIAYWLHPRTSAQIHLLGNIVIW
  VSGSLALAIYALLSLWYLLRRRRNVHDLPQDAWLRWVLAGALCAGGWAVNYLPFFLMEKT
  LFLYHYLPALTFQILLLPVVLQHISDHLCRSQLQRSIFSALVVAWYSSACHVSNTLRPLT
  YGDKSLSPHELKALRWKDSWDILIRKH
• Function: Transfers mannosyl residues to the hydroxyl group of serine or threonine residues. Coexpression of both POMT1 and POMT2 is necessary for enzyme activity, expression of either POMT1 or POMT2 alone is insufficient. Essentially dedicated to O-mannosylation of alpha-DAG1 and few other proteins but not of cadherins and protocaherins.
• Tissue Specificity: Widely expressed. Highly expressed in testis, heart and pancreas. Detected at lower levels in kidney, skeletal muscle, brain, placenta, lung and liver.
• KEGG Pathway:
  Other types of O-glycan biosynthesis (hsa00514)
  Mannose type O-glycan biosynthesis (hsa00515)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1 (R-HSA-5083633)
  O-linked glycosylation (R-HSA-5173105)
  Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2 (R-HSA-5083629)
• BioCyc Pathway: MetaCyc:HS05428-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

24 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 A1	DISQLATN	Definitive	Autosomal recessive	[1]
Myopathy caused by variation in POMT1	DISS717V	Definitive	Autosomal recessive	[2]
Autosomal recessive limb-girdle muscular dystrophy type 2A	DISIHX4S	Strong	Genetic Variation	[3]
Brain disease	DIS6ZC3X	Strong	Altered Expression	[4]
Brain neoplasm	DISY3EKS	Strong	Genetic Variation	[4]
Campomelic dysplasia	DISVTW53	Strong	Biomarker	[5]
Cleft lip/palate	DIS14IG3	Strong	Biomarker	[6]
Cobblestone lissencephaly	DIS56826	Strong	Genetic Variation	[7]
Craniometaphyseal dysplasia, autosomal dominant	DISU12OO	Strong	Biomarker	[5]
Hydrocephalus	DISIZUF7	Strong	Genetic Variation	[8]
Limb-girdle muscular dystrophy	DISI9Y1Z	Strong	Genetic Variation	[9]
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1	DISW7ZEG	Strong	Autosomal recessive	[10]
Congenital muscular dystrophy	DISKY7OY	moderate	Genetic Variation	[9]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[9]
Muscular dystrophy	DISJD6P7	moderate	Genetic Variation	[11]
Neuromuscular disease	DISQTIJZ	moderate	Biomarker	[12]
Autosomal recessive limb-girdle muscular dystrophy type 2K	DIS0FJ08	Supportive	Autosomal recessive	[13]
Congenital muscular dystrophy with intellectual disability	DISWHF75	Supportive	Autosomal recessive	[14]
Muscle-eye-brain disease	DISJUOQB	Supportive	Autosomal recessive	[15]
Muscular dystrophy-dystroglycanopathy, type A	DISZTBC4	Supportive	Autosomal recessive	[16]
Obsolete congenital muscular dystrophy with cerebellar involvement	DIS8CGS1	Supportive	Autosomal recessive	[14]
Obsolete congenital muscular dystrophy without intellectual disability	DISGKCTZ	Supportive	Autosomal recessive	[14]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[17]
Isolated congenital microcephaly	DISUXHZ6	Limited	Genetic Variation	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein O-mannosyl-transferase 1 (POMT1).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein O-mannosyl-transferase 1 (POMT1).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein O-mannosyl-transferase 1 (POMT1).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein O-mannosyl-transferase 1 (POMT1).	[21]
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the expression of Protein O-mannosyl-transferase 1 (POMT1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein O-mannosyl-transferase 1 (POMT1).	[23]

References

• [1] 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.
• [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] An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene.Neuromuscul Disord. 2005 Apr;15(4):271-5. doi: 10.1016/j.nmd.2005.01.013.
• [4] Genetic alterations of protein-o-mannosyltransferase-1 in glioneuronal and glial brain tumors with subarachnoid spread.Neuropathology. 2009 Apr;29(2):116-24. doi: 10.1111/j.1440-1789.2008.00954.x. Epub 2008 Jul 20.
• [5] Skeletal muscle MRI of the lower limbs in congenital muscular dystrophy patients with novel POMT1 and POMT2 mutations.Neuromuscul Disord. 2014 Apr;24(4):321-4. doi: 10.1016/j.nmd.2014.01.009. Epub 2014 Jan 28.
• [6] Walker-Warburg Syndrome with POMT1 mutations can be associated with cleft lip and cleft palate.Neuromuscul Disord. 2008 Aug;18(8):675-7. doi: 10.1016/j.nmd.2008.05.014. Epub 2008 Jul 18.
• [7] 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.
• [8] Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders.Orphanet J Rare Dis. 2019 Jul 16;14(1):179. doi: 10.1186/s13023-019-1119-0.
• [9] Analysis of phenotype, enzyme activity and genotype of Chinese patients with POMT1 mutation.J Hum Genet. 2016 Aug;61(8):753-9. doi: 10.1038/jhg.2016.42. Epub 2016 May 19.
• [10] Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet. 2002 Nov;71(5):1033-43. doi: 10.1086/342975. Epub 2002 Oct 4.
• [11] Molecular genetics of the POMT1-related muscular dystrophy-dystroglycanopathies.Mutat Res Rev Mutat Res. 2018 Oct-Dec;778:45-50. doi: 10.1016/j.mrrev.2018.09.002. Epub 2018 Sep 12.
• [12] Just Expect It: Compound Heterozygous Variants of POMT1 in a Consanguineous Family-The Role of Next Generation Sequencing in Neuromuscular Disorders.Neuropediatrics. 2020 Feb;51(1):72-75. doi: 10.1055/s-0039-1695787. Epub 2019 Oct 18.
• [13] Limb-Girdle Muscular Dystrophy Overview C RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2000 Jun 8 [updated 2012 Aug 30]. 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.
• [14] 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.
• [15] Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology. 2009 May 26;72(21):1802-9. doi: 10.1212/01.wnl.0000346518.68110.60. Epub 2009 Mar 18.
• [16] Role of N-glycans in maintaining the activity of protein O-mannosyltransferases POMT1 and POMT2. J Biochem. 2010 Mar;147(3):337-44. doi: 10.1093/jb/mvp170. Epub 2009 Oct 29.
• [17] Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy.Eur J Hum Genet. 2012 Dec;20(12):1234-9. doi: 10.1038/ejhg.2012.71. Epub 2012 May 2.
• [18] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [21] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [22] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [23] 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.