Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO1ZQZX)

• DOT Name: Protein O-mannosyl-transferase 2 (POMT2)
• Synonyms: EC 2.4.1.109; Dolichyl-phosphate-mannose--protein mannosyltransferase 2
• Gene Name: POMT2
• Related Disease:
  Campomelic dysplasia
  Craniometaphyseal dysplasia, autosomal dominant
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2
  Myopathy caused by variation in POMT2
  Cobblestone lissencephaly
  Intellectual disability
  Isolated congenital microcephaly
  Limb-girdle muscular dystrophy
  Muscular dystrophy
  Congenital muscular dystrophy
  Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2
  Autosomal recessive limb-girdle muscular dystrophy type 2N
  Congenital muscular dystrophy with intellectual disability
  Muscle-eye-brain disease
  Muscular dystrophy-dystroglycanopathy, type A
  Obsolete congenital muscular dystrophy with cerebellar involvement
  Advanced cancer
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4
• UniProt ID: POMT2_HUMAN
• EC Number: 2.4.1.109
• Pfam ID: PF02815 ; PF02366 ; PF16192
• Sequence:
  MPPATGGGLAESELRPRRGRCGPQAARAAGRDVAAEAVARSPKRPAWGSRRFEAVGWWAL
  LALVTLLSFATRFHRLDEPPHICWDETHFGKMGSYYINRTFFFDVHPPLGKMLIGLAGYL
  SGYDGTFLFQKPGDKYEHHSYMGMRGFCAFLGSWLVPFAYLTVLDLSKSLSAALLTAALL
  TFDTGCLTLSQYILLDPILMFFIMAAMLSMVKYNSCADRPFSAPWWFWLSLTGVSLAGAL
  GVKFVGLFIILQVGLNTIADLWYLFGDLSLSLVTVGKHLTARVLCLIVLPLALYTATFAV
  HFMVLSKSGPGDGFFSSAFQARLSGNNLHNASIPEHLAYGSVITVKNLRMAIGYLHSHRH
  LYPEGIGARQQQVTTYLHKDYNNLWIIKKHNTNSDPLDPSFPVEFVRHGDIIRLEHKETS
  RNLHSHYHEAPMTRKHYQVTGYGINGTGDSNDFWRIEVVNRKFGNRIKVLRSRIRFIHLV
  TGCVLGSSGKVLPKWGWEQLEVTCTPYLKETLNSIWNVEDHINPKLPNISLDVLQPSFPE
  ILLESHMVMIRGNSGLKPKDNEFTSKPWHWPINYQGLRFSGVNDTDFRVYLLGNPVVWWL
  NLLSIALYLLSGSIIAVAMQRGARLPAEVAGLSQVLLRGGGQVLLGWTLHYFPFFLMGRV
  LYFHHYFPAMLFSSMLTGILWDTLLRLCAWGLASWPLARGIHVAGILSLLLGTAYSFYLF
  HPLAYGMVGPLAQDPQSPMAGLRWLDSWDF
• 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: Highly expressed in testis; detected at low levels in most tissues.
• 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:HS00268-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Campomelic dysplasia	DISVTW53	Definitive	Genetic Variation	[1]
Craniometaphyseal dysplasia, autosomal dominant	DISU12OO	Definitive	Genetic Variation	[1]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2	DISPPX84	Definitive	Autosomal recessive	[2]
Myopathy caused by variation in POMT2	DISRHLQP	Definitive	Autosomal recessive	[3]
Cobblestone lissencephaly	DIS56826	Strong	Genetic Variation	[4]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[1]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[5]
Limb-girdle muscular dystrophy	DISI9Y1Z	Strong	Biomarker	[6]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[7]
Congenital muscular dystrophy	DISKY7OY	moderate	Genetic Variation	[8]
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2	DIS2BGID	Moderate	Autosomal recessive	[9]
Autosomal recessive limb-girdle muscular dystrophy type 2N	DISYOWK1	Supportive	Autosomal recessive	[10]
Congenital muscular dystrophy with intellectual disability	DISWHF75	Supportive	Autosomal recessive	[11]
Muscle-eye-brain disease	DISJUOQB	Supportive	Autosomal recessive	[12]
Muscular dystrophy-dystroglycanopathy, type A	DISZTBC4	Supportive	Autosomal recessive	[13]
Obsolete congenital muscular dystrophy with cerebellar involvement	DIS8CGS1	Supportive	Autosomal recessive	[11]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[14]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	DISGM0K5	Limited	Genetic Variation	[15]

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 Protein O-mannosyl-transferase 2 (POMT2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein O-mannosyl-transferase 2 (POMT2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein O-mannosyl-transferase 2 (POMT2).	[17]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Protein O-mannosyl-transferase 2 (POMT2).	[19]

References

• [1] 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.
• [2] POMT2 mutation in a patient with 'MEB-like' phenotype. Neuromuscul Disord. 2006 Jul;16(7):446-8. doi: 10.1016/j.nmd.2006.03.016. Epub 2006 May 15.
• [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] 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.
• [5] POMT1 and POMT2 mutations in CMD patients: a multicentric Italian study.Neuromuscul Disord. 2008 Jul;18(7):565-71. doi: 10.1016/j.nmd.2008.04.004. Epub 2008 Jun 2.
• [6] Limb girdle muscular dystrophy due to mutations in POMT2.J Neurol Neurosurg Psychiatry. 2018 May;89(5):506-512. doi: 10.1136/jnnp-2017-317018. Epub 2017 Nov 24.
• [7] Heterozygous deletion of a 2-Mb region including the dystroglycan gene in a patient with mild myopathy, facial hypotonia, oral-motor dyspraxia and white matter abnormalities.Eur J Hum Genet. 2010 Jul;18(7):852-5. doi: 10.1038/ejhg.2010.28. Epub 2010 Mar 17.
• [8] Novel cardiovascular findings in association with a POMT2 mutation: three siblings with -dystroglycanopathy.Eur J Hum Genet. 2014 Apr;22(4):486-91. doi: 10.1038/ejhg.2013.165. Epub 2013 Sep 4.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Genome-wide expression analysis reveals six contravened targets of EZH2 associated with breast cancer patient survival.Sci Rep. 2019 Feb 13;9(1):1974. doi: 10.1038/s41598-019-39122-4.
• [15] Muscular dystrophies due to glycosylation defects.Neurotherapeutics. 2008 Oct;5(4):627-32. doi: 10.1016/j.nurt.2008.08.005.
• [16] 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.
• [17] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [18] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [19] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.