Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW7PENS)

• DOT Name: Kin of IRRE-like protein 3 (KIRREL3)
• Synonyms: Kin of irregular chiasm-like protein 3; Nephrin-like protein 2
• Gene Name: KIRREL3
• Related Disease:
  Autism
  Intellectual disability
  Neurodevelopmental disorder
  Osteoarthritis
  Autism spectrum disorder
  Gastrointestinal stromal tumour
  Autosomal dominant non-syndromic intellectual disability
  Complex neurodevelopmental disorder
  Intellectual disability, autosomal dominant 4
  Pervasive developmental disorder
• UniProt ID: KIRR3_HUMAN
• PDB ID: 2CRY
• Pfam ID: PF08205 ; PF07679 ; PF13927
• Sequence:
  MKPFQLDLLFVCFFLFSQELGLQKRGCCLVLGYMAKDKFRRMNEGQVYSFSQQPQDQVVV
  SGQPVTLLCAIPEYDGFVLWIKDGLALGVGRDLSSYPQYLVVGNHLSGEHHLKILRAELQ
  DDAVYECQAIQAAIRSRPARLTVLVPPDDPVILGGPVISLRAGDPLNLTCHADNAKPAAS
  IIWLRKGEVINGATYSKTLLRDGKRESIVSTLFISPGDVENGQSIVCRATNKAIPGGKET
  SVTIDIQHPPLVNLSVEPQPVLEDNVVTFHCSAKANPAVTQYRWAKRGQIIKEASGEVYR
  TTVDYTYFSEPVSCEVTNALGSTNLSRTVDVYFGPRMTTEPQSLLVDLGSDAIFSCAWTG
  NPSLTIVWMKRGSGVVLSNEKTLTLKSVRQEDAGKYVCRAVVPRVGAGEREVTLTVNGPP
  IISSTQTQHALHGEKGQIKCFIRSTPPPDRIAWSWKENVLESGTSGRYTVETISTEEGVI
  STLTISNIVRADFQTIYNCTAWNSFGSDTEIIRLKEQGSEMKSGAGLEAESVPMAVIIGV
  AVGAGVAFLVLMATIVAFCCARSQRNLKGVVSAKNDIRVEIVHKEPASGREGEEHSTIKQ
  LMMDRGEFQQDSVLKQLEVLKEEEKEFQNLKDPTNGYYSVNTFKEHHSTPTISLSSCQPD
  LRPAGKQRVPTGMSFTNIYSTLSGQGRLYDYGQRFVLGMGSSSIELCEREFQRGSLSDSS
  SFLDTQCDSSVSSSGKQDGYVQFDKASKASASSSHHSQSSSQNSDPSRPLQRRMQTHV
• Function: Synaptic adhesion molecule required for the formation of target-specific synapses. Required for formation of target-specific synapses at hippocampal mossy fiber synapses. Required for formation of mossy fiber filopodia, the synaptic structures connecting dentate granule and GABA neurons. Probably acts as a homophilic adhesion molecule that promotes trans-cellular interactions and stabilize mossy fiber filipodia contact and subsequent synapse formation. Required for the coalescence of vomeronasal sensory neuron axons. May be involved in the hematopoietic supportive capacity of stroma cells; the secreted extracellular domain is directly responsible for supporting hematopoietic stem cells.
• Tissue Specificity: Expressed in fetal and adult brain . Also expressed in kidney, specifically in podocytes of kidney glomeruli . Also expressed in skeletal muscle .
• Reactome Pathway: Nephrin family interactions (R-HSA-373753)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Biomarker	[1]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[2]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[2]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[3]
Autism spectrum disorder	DISXK8NV	moderate	Genetic Variation	[2]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[4]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[5]
Complex neurodevelopmental disorder	DISB9AFI	Disputed	Autosomal dominant	[6]
Intellectual disability, autosomal dominant 4	DISNHOJN	Limited	Unknown	[7]
Pervasive developmental disorder	DIS51975	Limited	Biomarker	[8]

6 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 Kin of IRRE-like protein 3 (KIRREL3).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Kin of IRRE-like protein 3 (KIRREL3).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Kin of IRRE-like protein 3 (KIRREL3).	[11]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Kin of IRRE-like protein 3 (KIRREL3).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Kin of IRRE-like protein 3 (KIRREL3).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Kin of IRRE-like protein 3 (KIRREL3).	[15]

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 decreases the methylation of Kin of IRRE-like protein 3 (KIRREL3).	[13]

References

• [1] Neph2/Kirrel3 regulates sensory input, motor coordination, and home-cage activity in rodents.Genes Brain Behav. 2018 Nov;17(8):e12516. doi: 10.1111/gbb.12516. Epub 2018 Sep 14.
• [2] Abnormal behaviours relevant to neurodevelopmental disorders in Kirrel3-knockout mice.Sci Rep. 2018 Jan 23;8(1):1408. doi: 10.1038/s41598-018-19844-7.
• [3] Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study.Lancet. 2012 Sep 1;380(9844):815-23. doi: 10.1016/S0140-6736(12)60681-3. Epub 2012 Jul 3.
• [4] Gene expression of the IGF pathway family distinguishes subsets of gastrointestinal stromal tumors wild type for KIT and PDGFRA.Cancer Med. 2013 Feb;2(1):21-31. doi: 10.1002/cam4.57. Epub 2013 Feb 3.
• [5] Alterations in CDH15 and KIRREL3 in patients with mild to severe intellectual disability. Am J Hum Genet. 2008 Dec;83(6):703-13. doi: 10.1016/j.ajhg.2008.10.020. Epub 2008 Nov 13.
• [6] 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.
• [7] Speech and language development of children with Down's syndrome. Dev Med Child Neurol. 1978 Feb;20(1):106-9. doi: 10.1111/j.1469-8749.1978.tb15189.x.
• [8] Autism and Intellectual Disability-Associated KIRREL3 Interacts with Neuronal Proteins MAP1B and MYO16 with Potential Roles in Neurodevelopment.PLoS One. 2015 Apr 22;10(4):e0123106. doi: 10.1371/journal.pone.0123106. eCollection 2015.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [13] 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.
• [14] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.