Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE2P8G0)

• DOT Name: Signal-regulatory protein gamma (SIRPG)
• Synonyms: SIRP-gamma; CD172 antigen-like family member B; Signal-regulatory protein beta-2; SIRP-b2; SIRP-beta-2; CD antigen CD172g
• Gene Name: SIRPG
• Related Disease:
  Autoimmune disease
  Multiple sclerosis
  Oligospermia
  Systemic lupus erythematosus
  Type-1 diabetes
  Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation
• UniProt ID: SIRPG_HUMAN
• PDB ID: 2JJW; 4I2X
• Pfam ID: PF07654 ; PF07686
• Sequence:
  MPVPASWPHPPGPFLLLTLLLGLTEVAGEEELQMIQPEKLLLVTVGKTATLHCTVTSLLP
  VGPVLWFRGVGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCV
  KFRKGSPENVEFKSGPGTEMALGAKPSAPVVLGPAARTTPEHTVSFTCESHGFSPRDITL
  KWFKNGNELSDFQTNVDPTGQSVAYSIRSTARVVLDPWDVRSQVICEVAHVTLQGDPLRG
  TANLSEAIRVPPTLEVTQQPMRVGNQVNVTCQVRKFYPQSLQLTWSENGNVCQRETASTL
  TENKDGTYNWTSWFLVNISDQRDDVVLTCQVKHDGQLAVSKRLALEVTVHQKDQSSDATP
  GPASSLTALLLIAVLLGPIYVPWKQKT
• Function: Probable immunoglobulin-like cell surface receptor. On binding with CD47, mediates cell-cell adhesion. Engagement on T-cells by CD47 on antigen-presenting cells results in enhanced antigen-specific T-cell proliferation and costimulates T-cell activation.
• Tissue Specificity: Detected in liver, and at very low levels in brain, heart, lung, pancreas, kidney, placenta and skeletal muscle. Expressed on CD4+ T-cells, CD8+ T-cells, CD56-bright natural killer (NK) cells, CD20+ cells, and all activated NK cells. Mainly present in the paracortical T-cell area of lymph nodes, with only sparse positive cells in the mantle and in the germinal center of B-cell follicles. In the thymus, primarily expressed in the medulla on mature T-lymphocytes that have undergone thymic selection.
• KEGG Pathway:
  Efferocytosis (hsa04148)
  Osteoclast differentiation (hsa04380)
• Reactome Pathway:
  Signal regulatory protein family interactions (R-HSA-391160)
  Cell surface interactions at the vascular wall (R-HSA-202733)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[1]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[2]
Oligospermia	DIS6YJF3	Strong	Genetic Variation	[3]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[4]
Type-1 diabetes	DIS7HLUB	Strong	Altered Expression	[1]
Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation	DIS56JR8	Limited	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Signal-regulatory protein gamma (SIRPG).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Signal-regulatory protein gamma (SIRPG).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Signal-regulatory protein gamma (SIRPG).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Signal-regulatory protein gamma (SIRPG).	[9]

References

• [1] Autoimmunity-associated intronic SNP (rs2281808) detected by a simple phenotypic assay: Unique case or broader opportunity?.Clin Immunol. 2019 Jan;198:57-61. doi: 10.1016/j.clim.2018.12.018. Epub 2018 Dec 21.
• [2] Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011 Dec;70(6):897-912. doi: 10.1002/ana.22609.
• [3] Evaluation of five candidate genes from GWAS for association with oligozoospermia in a Han Chinese population.PLoS One. 2013 Nov 26;8(11):e80374. doi: 10.1371/journal.pone.0080374. eCollection 2013.
• [4] Changes in the gene expression of peripheral blood mononuclear cells during the menstrual cycle of females is associated with a gender bias in the incidence of systemic lupus erythematosus.Clin Exp Rheumatol. 2009 Mar-Apr;27(2):260-6.
• [5] A genomics approach to male infertility. Genet Med. 2020 Dec;22(12):1967-1975. doi: 10.1038/s41436-020-0916-0. Epub 2020 Jul 28.
• [6] 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.
• [7] 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.
• [8] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.