Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMF1PZW)

• DOT Name: AF4/FMR2 family member 2 (AFF2)
• Synonyms: Protein FMR-2; FMR2P; Protein Ox19
• Gene Name: AFF2
• Related Disease:
  FRAXE intellectual disability
  Non-syndromic X-linked intellectual disability
  Acute leukaemia
  Acute lymphocytic leukaemia
  Coffin-Lowry syndrome
  Intellectual disability, X-linked 19
  Mucopolysaccharidosis II
  Pervasive developmental disorder
  X-linked intellectual disability
  CHARGE syndrome
  Cognitive impairment
  Epilepsy
  Female hypogonadism
  Amyotrophic lateral sclerosis
  Frontotemporal dementia
  Autism spectrum disorder
  Fragile X syndrome
  Intellectual disability, X-linked 1
  Parkinson disease
  T-cell acute lymphoblastic leukaemia
• UniProt ID: AFF2_HUMAN
• Pfam ID: PF05110 ; PF18875 ; PF18876
• Sequence:
  MDLFDFFRDWDLEQQCHYEQDRSALKKREWERRNQEVQQEDDLFSSGFDLFGEPYKVAEY
  TNKGDALANRVQNTLGNYDEMKNLLTNHSNQNHLVGIPKNSVPQNPNNKNEPSFFPEQKN
  RIIPPHQDNTHPSAPMPPPSVVILNSTLIHSNRKSKPEWSRDSHNPSTVLASQASGQPNK
  MQTLTQDQSQAKLEDFFVYPAEQPQIGEVEESNPSAKEDSNPNSSGEDAFKEIFQSNSPE
  ESEFAVQAPGSPLVASSLLAPSSGLSVQNFPPGLYCKTSMGQQKPTAYVRPMDGQDQAPD
  ISPTLKPSIEFENSFGNLSFGTLLDGKPSAASSKTKLPKFTILQTSEVSLPSDPSCVEEI
  LREMTHSWPTPLTSMHTAGHSEQSTFSIPGQESQHLTPGFTLQKWNDPTTRASTKSVSFK
  SMLEDDLKLSSDEDDLEPVKTLTTQCTATELYQAVEKAKPRNNPVNPPLATPQPPPAVQA
  SGGSGSSSESESSSESDSDTESSTTDSESNEAPRVATPEPEPPSTNKWQLDKWLNKVTSQ
  NKSFICGQNETPMETISLPPPIIQPMEVQMKVKTNASQVPAEPKERPLLSLIREKARPRP
  TQKIPETKALKHKLSTTSETVSQRTIGKKQPKKVEKNTSTDEFTWPKPNITSSTPKEKES
  VELHDPPRGRNKATAHKPAPRKEPRPNIPLAPEKKKYRGPGKIVPKSREFIETDSSTSDS
  NTDQEETLQIKVLPPCIISGGNTAKSKEICGASLTLSTLMSSSGSNNNLSISNEEPTFSP
  IPVMQTEILSPLRDHENLKNLWVKIDLDLLSRVPGHSSLHAAPAKPDHKETATKPKRQTA
  VTAVEKPAPKGKRKHKPIEVAEKIPEKKQRLEEATTICLLPPCISPAPPHKPPNTRENNS
  SRRANRRKEEKLFPPPLSPLPEDPPRRRNVSGNNGPFGQDKNIAMTGQITSTKPKRTEGK
  FCATFKGISVNEGDTPKKASSATITVTNTAIATATVTATAIVTTTVTATATATATTTTTT
  TTISTITSTITTGLMDSSHLEMTSWAALPLLSSSSTNVRRPKLTFDDSVHNADYYMQEAK
  KLKHKADALFEKFGKAVNYADAALSFTECGNAMERDPLEAKSPYTMYSETVELLRYAMRL
  KNFASPLASDGDKKLAVLCYRCLSLLYLRMFKLKKDHAMKYSRSLMEYFKQNASKVAQIP
  SPWVSNGKNTPSPVSLNNVSPINAMGNCNNGPVTIPQRIHHMAASHVNITSNVLRGYEHW
  DMADKLTRENKEFFGDLDTLMGPLTQHSSMTNLVRYVRQGLCWLRIDAHLL
• Function: RNA-binding protein. Might be involved in alternative splicing regulation through an interaction with G-quartet RNA structure.
• Tissue Specificity: Brain (most abundant in hippocampus and amygdala), placenta and lung.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
FRAXE intellectual disability	DISDPS6G	Definitive	X-linked	[1]
Non-syndromic X-linked intellectual disability	DIS71AI3	Definitive	X-linked	[2]
Acute leukaemia	DISDQFDI	Strong	Genetic Variation	[3]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[4]
Coffin-Lowry syndrome	DISMTBDA	Strong	Genetic Variation	[5]
Intellectual disability, X-linked 19	DIS240KZ	Strong	Biomarker	[5]
Mucopolysaccharidosis II	DIS87GLG	Strong	Genetic Variation	[6]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[7]
X-linked intellectual disability	DISYJBY3	Strong	Biomarker	[8]
CHARGE syndrome	DISKD3CW	moderate	Biomarker	[9]
Cognitive impairment	DISH2ERD	moderate	Biomarker	[9]
Epilepsy	DISBB28L	moderate	Biomarker	[9]
Female hypogonadism	DISWASB4	moderate	Biomarker	[10]
Amyotrophic lateral sclerosis	DISF7HVM	Disputed	Biomarker	[11]
Frontotemporal dementia	DISKYHXL	Disputed	Altered Expression	[11]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[12]
Fragile X syndrome	DISE8W3A	Limited	Biomarker	[9]
Intellectual disability, X-linked 1	DISET38E	Limited	Biomarker	[8]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[13]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Genetic Variation	[14]

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 AF4/FMR2 family member 2 (AFF2).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of AF4/FMR2 family member 2 (AFF2).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of AF4/FMR2 family member 2 (AFF2).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of AF4/FMR2 family member 2 (AFF2).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of AF4/FMR2 family member 2 (AFF2).	[20]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of AF4/FMR2 family member 2 (AFF2).	[21]

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 AF4/FMR2 family member 2 (AFF2).	[18]

References

• [1] Familial intellectual disability and autistic behavior caused by a small FMR2 gene deletion. Am J Med Genet A. 2011 Aug;155A(8):2003-7. doi: 10.1002/ajmg.a.34122. Epub 2011 Jul 7.
• [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] Exon/intron structure of the human AF-4 gene, a member of the AF-4/LAF-4/FMR-2 gene family coding for a nuclear protein with structural alterations in acute leukaemia.Br J Haematol. 1997 Jul;98(1):157-69. doi: 10.1046/j.1365-2141.1997.1522966.x.
• [4] Functional characterization of the AFF (AF4/FMR2) family of RNA-binding proteins: insights into the molecular pathology of FRAXE intellectual disability.Hum Mol Genet. 2011 May 15;20(10):1873-85. doi: 10.1093/hmg/ddr069. Epub 2011 Feb 17.
• [5] Regional localization of an X-linked mental retardation gene to Xp21.1-Xp22.13 (MRX38).Am J Med Genet. 1996 Jul 12;64(1):89-96. doi: 10.1002/(SICI)1096-8628(19960712)64:1<89::AID-AJMG16>3.0.CO;2-O.
• [6] Severe Hunter syndrome (mucopolysaccharidosis II) phenotype secondary to large deletion in the X chromosome encompassing IDS, FMR1, and AFF2 (FMR2).J Child Neurol. 2012 Jun;27(6):786-90. doi: 10.1177/0883073811425860. Epub 2011 Dec 21.
• [7] Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder.Hum Mol Genet. 2012 Oct 1;21(19):4356-64. doi: 10.1093/hmg/dds267. Epub 2012 Jul 5.
• [8] Fragile XE-associated familial mental retardation protein 2 (FMR2) acts as a potent transcription activator.J Hum Genet. 2001;46(5):251-9. doi: 10.1007/s100380170074.
• [9] Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.Am J Hum Genet. 2013 Aug 8;93(2):249-63. doi: 10.1016/j.ajhg.2013.06.012. Epub 2013 Jul 11.
• [10] Distribution of FMR1 and FMR2 Repeats in Argentinean Patients with Primary Ovarian Insufficiency.Genes (Basel). 2017 Aug 16;8(8):194. doi: 10.3390/genes8080194.
• [11] Transcription elongation factor AFF2/FMR2 regulates expression of expanded GGGGCC repeat-containing C9ORF72 allele in ALS/FTD.Nat Commun. 2019 Nov 29;10(1):5466. doi: 10.1038/s41467-019-13477-8.
• [12] Fetal DNA methylation of autism spectrum disorders candidate genes: association with spontaneous preterm birth.Am J Obstet Gynecol. 2015 Apr;212(4):533.e1-9. doi: 10.1016/j.ajog.2015.02.011. Epub 2015 Feb 14.
• [13] Intermediate alleles at the FRAXA and FRAXE loci in Parkinson's disease.Parkinsonism Relat Disord. 2011 May;17(4):281-4. doi: 10.1016/j.parkreldis.2010.12.013. Epub 2011 Jan 22.
• [14] Identification of the novel AML1 fusion partner gene, LAF4, a fusion partner of MLL, in childhood T-cell acute lymphoblastic leukemia with t(2;21)(q11;q22) by bubble PCR method for cDNA.Oncogene. 2008 Apr 3;27(15):2249-56. doi: 10.1038/sj.onc.1210857. Epub 2007 Oct 29.
• [15] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [16] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] 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.
• [19] 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.
• [20] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [21] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.