Details of Drug Off-Target (DOT)

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

• DOT Name: Septin-12 (SEPTIN12)
• Gene Name: SEPTIN12
• Related Disease:
  Azoospermia
  Oligospermia
  Male infertility
  Obsolete non-syndromic male infertility due to sperm motility disorder
  Spermatogenic failure 10
• UniProt ID: SEP12_HUMAN
• PDB ID: 6MQ9; 6MQB; 6MQK; 6MQL
• Pfam ID: PF00735
• Sequence:
  MDPLRRSPSPCLSSQPSSPSTPPCEMLGPVGIEAVLDQLKIKAMKMGFEFNIMVVGQSGL
  GKSTMVNTLFKSKVWKSNPPGLGVPTPQTLQLHSLTHVIEEKGVKLKLTVTDTPGFGDQI
  NNDNCWDPILGYINEQYEQYLQEEILITRQRHIPDTRVHCCVYFVPPTGHCLRPLDIEFL
  QRLCRTVNVVPVIARADSLTMEEREAFRRRIQQNLRTHCIDVYPQMCFDEDINDKILNSK
  LRDRIPFAVVGADQEHLVNGRCVLGRKTKWGIIEVENMAHCEFPLLRDLLIRSHLQDLKD
  ITHNIHYENYRVIRLNESHLLPRGPGWVNLAPASPGQLTTPRTFKVCRGAHDDSDDEF
• Function: Filament-forming cytoskeletal GTPase. Involved in spermatogenesis. Involved in the morphogenesis of sperm heads and the elongation of sperm tails probably implicating the association with alpha- and beta-tubulins. Forms a filamentous structure with SEPTIN7, SEPTIN6, SEPTIN2 and probably SEPTIN4 at the sperm annulus which is required for the structural integrity and motility of the sperm tail during postmeiotic differentiation. May play a role in cytokinesis (Potential).
• Tissue Specificity: Widely expressed. Expressed in lymph node.
• KEGG Pathway:
  Bacterial invasion of epithelial cells (hsa05100)
  Shigellosis (hsa05131)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Azoospermia	DIS94181	Strong	Genetic Variation	[1]
Oligospermia	DIS6YJF3	Strong	Biomarker	[2]
Male infertility	DISY3YZZ	moderate	Genetic Variation	[3]
Obsolete non-syndromic male infertility due to sperm motility disorder	DISG7641	Supportive	Autosomal recessive	[4]
Spermatogenic failure 10	DISKGPQL	Limited	Autosomal dominant	[5]

3 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 Septin-12 (SEPTIN12).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Septin-12 (SEPTIN12).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Septin-12 (SEPTIN12).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Septin-12 (SEPTIN12).	[7]

References

• [1] Single nucleotide polymorphisms in the SEPTIN12 gene may be associated with azoospermia by meiotic arrest in Japanese men.J Assist Reprod Genet. 2012 Jan;29(1):47-51. doi: 10.1007/s10815-011-9679-5. Epub 2011 Nov 25.
• [2] SEPT12-NDC1 Complexes Are Required for Mammalian Spermiogenesis.Int J Mol Sci. 2016 Nov 16;17(11):1911. doi: 10.3390/ijms17111911.
• [3] Association of single nucleotide polymorphism c.673C>A/p.Gln225Lys in SEPT12 gene with spermatogenesis failure in male idiopathic infertility in Northeast China.J Int Med Res. 2019 Feb;47(2):992-998. doi: 10.1177/0300060518811770. Epub 2018 Nov 29.
• [4] SEPT12 mutations cause male infertility with defective sperm annulus. Hum Mutat. 2012 Apr;33(4):710-9. doi: 10.1002/humu.22028. Epub 2012 Feb 20.
• [5] SEPT12 deficiency causes sperm nucleus damage and developmental arrest of preimplantation embryos. Fertil Steril. 2011 Jan;95(1):363-5. doi: 10.1016/j.fertnstert.2010.07.1064.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] 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.