Details of Drug Off-Target (DOT)

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

• DOT Name: Tetratricopeptide repeat protein 7A (TTC7A)
• Synonyms: TPR repeat protein 7A
• Gene Name: TTC7A
• Related Disease:
  Gastrointestinal defects and immunodeficiency syndrome 1
  Multiple intestinal atresia
  Alopecia
  Alzheimer disease
  Anemia
  Chronic intestinal pseudoobstruction
  Dermatitis
  Enterocolitis
  Erectile dysfunction
  Immunodeficiency
  Prostate carcinoma
  Psoriasis
  Severe combined immunodeficiency
  Trichohepatoenteric syndrome
  Ventricular septal defect
  Immune system disorder
  Inflammatory bowel disease
  Intestinal disorder
• UniProt ID: TTC7A_HUMAN
• Pfam ID: PF13181 ; PF19440
• Sequence:
  MAAKGAHGSYLKVESELERCRAEGHWDRMPELVRQLQTLSMPGGGGNRRGSPSAAFTFPD
  TDDFGKLLLAEALLEQCLKENHAKIKDSMPLLEKNEPKMSEAKNYLSSILNHGRLSPQYM
  CEAMLILGKLHYVEGSYRDAISMYARAGIDDMSMENKPLYQMRLLSEAFVIKGLSLERLP
  NSIASRFRLTEREEEVITCFERASWIAQVFLQELEKTTNNSTSRHLKGCHPLDYELTYFL
  EAALQSAYVKNLKKGNIVKGMRELREVLRTVETKATQNFKVMAAKHLAGVLLHSLSEECY
  WSPLSHPLPEFMGKEESSFATQALRKPHLYEGDNLYCPKDNIEEALLLLLISESMATRDV
  VLSRVPEQEEDRTVSLQNAAAIYDLLSITLGRRGQYVMLSECLERAMKFAFGEFHLWYQV
  ALSMVACGKSAYAVSLLRECVKLRPSDPTVPLMAAKVCIGSLRWLEEAEHFAMMVISLGE
  EAGEFLPKGYLALGLTYSLQATDATLKSKQDELHRKALQTLERAQQLAPSDPQVILYVSL
  QLALVRQISSAMEQLQEALKVRKDDAHALHLLALLFSAQKHHQHALDVVNMAITEHPENF
  NLMFTKVKLEQVLKGPEEALVTCRQVLRLWQTLYSFSQLGGLEKDGSFGEGLTMKKQSGM
  HLTLPDAHDADSGSRRASSIAASRLEEAMSELTMPSSVLKQGPMQLWTTLEQIWLQAAEL
  FMEQQHLKEAGFCIQEAAGLFPTSHSVLYMRGRLAEVKGNLEEAKQLYKEALTVNPDGVR
  IMHSLGLMLSRLGHKSLAQKVLRDAVERQSTCHEAWQGLGEVLQAQGQNEAAVDCFLTAL
  ELEASSPVLPFSIIPREL
• Function: Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane. The complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (Probable). In the complex, plays a central role in bridging PI4KA to EFR3B and HYCC1, via direct interactions.
• Tissue Specificity: Expressed in epithelial cells of the intestine, thymus, and pancreas (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastrointestinal defects and immunodeficiency syndrome 1	DISKPTVU	Definitive	Autosomal recessive	[1]
Multiple intestinal atresia	DISNUH76	Definitive	Autosomal recessive	[2]
Alopecia	DIS37HU4	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Anemia	DISTVL0C	Strong	Genetic Variation	[5]
Chronic intestinal pseudoobstruction	DISR68AN	Strong	Biomarker	[6]
Dermatitis	DISY5SZC	Strong	Biomarker	[7]
Enterocolitis	DISYACTL	Strong	Genetic Variation	[8]
Erectile dysfunction	DISD8MTH	Strong	Genetic Variation	[9]
Immunodeficiency	DIS093I0	Strong	Genetic Variation	[6]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[9]
Psoriasis	DIS59VMN	Strong	Genetic Variation	[5]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Genetic Variation	[10]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[11]
Ventricular septal defect	DISICO41	Strong	CausalMutation	[12]
Immune system disorder	DISAEGPH	moderate	Genetic Variation	[13]
Inflammatory bowel disease	DISGN23E	Limited	Biomarker	[11]
Intestinal disorder	DISGPMUQ	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tetratricopeptide repeat protein 7A (TTC7A).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tetratricopeptide repeat protein 7A (TTC7A).	[16]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Tetratricopeptide repeat protein 7A (TTC7A).	[17]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Tetratricopeptide repeat protein 7A (TTC7A).	[18]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Tetratricopeptide repeat protein 7A (TTC7A).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tetratricopeptide repeat protein 7A (TTC7A).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tetratricopeptide repeat protein 7A (TTC7A).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Tetratricopeptide repeat protein 7A (TTC7A).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Tetratricopeptide repeat protein 7A (TTC7A).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tetratricopeptide repeat protein 7A (TTC7A).	[23]

References

• [1] Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia. J Med Genet. 2013 May;50(5):324-9. doi: 10.1136/jmedgenet-2012-101483. Epub 2013 Feb 19.
• [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] Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency.J Allergy Clin Immunol. 2014 Dec;134(6):1354-1364.e6. doi: 10.1016/j.jaci.2014.07.019. Epub 2014 Aug 28.
• [4] TTC7 and Hyccin Regulate Neuronal A42 Accumulation and its Associated Neural Deficits in A42-Expressing Drosophila.J Alzheimers Dis. 2018;65(3):1001-1010. doi: 10.3233/JAD-170907.
• [5] The Tetratricopeptide repeat domain 7 gene is mutated in flaky skin mice: a model for psoriasis, autoimmunity, and anemia.Exp Biol Med (Maywood). 2005 Oct;230(9):659-67. doi: 10.1177/153537020523000908.
• [6] Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency.Front Immunol. 2019 Nov 7;10:2592. doi: 10.3389/fimmu.2019.02592. eCollection 2019.
• [7] Epithelial proliferation in inflammatory skin disease is regulated by tetratricopeptide repeat domain 7 (Ttc7) in fibroblasts and lymphocytes.J Allergy Clin Immunol. 2019 Jan;143(1):292-304.e8. doi: 10.1016/j.jaci.2018.02.057. Epub 2018 Jun 14.
• [8] Multiple intestinal atresia with combined immune deficiency.Curr Opin Pediatr. 2014 Dec;26(6):690-6. doi: 10.1097/MOP.0000000000000159.
• [9] Genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer.Int J Radiat Oncol Biol Phys. 2010 Dec 1;78(5):1292-300. doi: 10.1016/j.ijrobp.2010.07.036.
• [10] Congenital intestinal atresias with multiple episodes of sepsis: A case report and review of literature.Medicine (Baltimore). 2018 Jun;97(23):e10939. doi: 10.1097/MD.0000000000010939.
• [11] Missense mutation of TTC7A mimicking tricho-hepato-enteric (SD/THE) syndrome in a patient with very-early onset inflammatory bowel disease.Eur J Med Genet. 2018 Apr;61(4):185-188. doi: 10.1016/j.ejmg.2017.11.014. Epub 2017 Nov 23.
• [12] A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders.Genet Med. 2016 Nov;18(11):1090-1096. doi: 10.1038/gim.2016.1. Epub 2016 Mar 3.
• [13] Tetratricopeptide repeat domain 7A is a nuclear factor that modulates transcription and chromatin structure.Cell Discov. 2018 Nov 13;4:61. doi: 10.1038/s41421-018-0061-y. eCollection 2018.
• [14] Drug Screen Identifies Leflunomide for Treatment of Inflammatory Bowel Disease Caused by TTC7A Deficiency.Gastroenterology. 2020 Mar;158(4):1000-1015. doi: 10.1053/j.gastro.2019.11.019. Epub 2019 Nov 16.
• [15] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [16] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [17] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [18] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [19] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [20] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [21] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [22] 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.
• [23] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [24] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.