Details of Drug Off-Target (DOT)

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

• DOT Name: Trafficking protein particle complex subunit 11 (TRAPPC11)
• Gene Name: TRAPPC11
• Related Disease:
  Autosomal recessive limb-girdle muscular dystrophy
  Autosomal recessive limb-girdle muscular dystrophy type R18
  Congenital disorder of glycosylation
  Movement disorder
  Congenital muscular dystrophy
  Intellectual disability
  Muscular dystrophy
  Intellectual disability-hyperkinetic movement-truncal ataxia syndrome
  Triple-A syndrome
  Limb-girdle muscular dystrophy
  Myopathy
  Systemic lupus erythematosus
• UniProt ID: TPC11_HUMAN
• Pfam ID: PF11817 ; PF12742
• Sequence:
  MSPTQWDFPVELCCRPMAFVTLTGLDVVYNAVHRAVWDAFCANRRADRVPISFKVLPGDH
  EYPKCRPKRTSYEWYIPKGILKTGWMNKHLNLVPALVVVFYELDWDEPQWKEKQSECATR
  VEIVRQSLQGRNTKVAVVLIQKKTPLPPGEDVIASERAAALCNACELSGKSLFVLPHTDH
  LVGYIIRLENAFYEHAQTYYYTEIRRVKSHKEFLNKTTHQLLFVRHQFKIAFFSELKQDT
  QNALKNYRTAYNLVHELRAHETNILEIKTMAGFINYKICRLCFQHNTPLDAIAQFRKHID
  LCKKKIGSAELSFEHDAWMSKQFQAFGDLFDEAIKLGLTAIQTQNPGFYYQQAAYYAQER
  KQLAKTLCNHEASVMYPNPDPLETQTGVLDFYGQRSWRQGILSFDLSDPEKEKVGILAIQ
  LKERNVVHSEIIITLLSNAVAQFKKYKCPRMKSHLMVQMGEEYYYAKDYTKALKLLDYVM
  CDYRSEGWWTLLTSVLTTALKCSYLMAQLKDYITYSLELLGRASTLKDDQKSRIEKNLIN
  VLMNESPDPEPDCDILAVKTAQKLWADRISLAGSNIFTIGVQDFVPFVQCKAKFHAPSFH
  VDVPVQFDIYLKADCPHPIRFSKLCVSFNNQEYNQFCVIEEASKANEVLENLTQGKMCLV
  PGKTRKLLFKFVAKTEDVGKKIEITSVDLALGNETGRCVVLNWQGGGGDAASSQEALQAA
  RSFKRRPKLPDNEVHWDSIIIQASTMIISRVPNISVHLLHEPPALTNEMYCLVVTVQSHE
  KTQIRDVKLTAGLKPGQDANLTQKTHVTLHGTELCDESYPALLTDIPVGDLHPGEQLEKM
  LYVRCGTVGSRMFLVYVSYLINTTVEEKEIVCKCHKDETVTIETVFPFDVAVKFVSTKFE
  HLERVYADIPFLLMTDLLSASPWALTIVSSELQLAPSMTTVDQLESQVDNVILQTGESAS
  ECFCLQCPSLGNIEGGVATGHYIISWKRTSAMENIPIITTVITLPHVIVENIPLHVNADL
  PSFGRVRESLPVKYHLQNKTDLVQDVEISVEPSDAFMFSGLKQIRLRILPGTEQEMLYNF
  YPLMAGYQQLPSLNINLLRFPNFTNQLLRRFIPTSIFVKPQGRLMDDTSIAAA
• Function: Involved in endoplasmic reticulum to Golgi apparatus trafficking at a very early stage.
• Reactome Pathway: RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive limb-girdle muscular dystrophy	DISWPGLM	Definitive	Autosomal recessive	[1]
Autosomal recessive limb-girdle muscular dystrophy type R18	DIS2BI41	Definitive	Autosomal recessive	[1]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[2]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[3]
Congenital muscular dystrophy	DISKY7OY	moderate	Genetic Variation	[4]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[3]
Muscular dystrophy	DISJD6P7	moderate	Genetic Variation	[4]
Intellectual disability-hyperkinetic movement-truncal ataxia syndrome	DISXZ0HQ	Supportive	Autosomal recessive	[3]
Triple-A syndrome	DISCOH2J	Supportive	Autosomal recessive	[5]
Limb-girdle muscular dystrophy	DISI9Y1Z	Disputed	Genetic Variation	[4]
Myopathy	DISOWG27	Disputed	Biomarker	[4]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[6]

1 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 Trafficking protein particle complex subunit 11 (TRAPPC11).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Trafficking protein particle complex subunit 11 (TRAPPC11).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Trafficking protein particle complex subunit 11 (TRAPPC11).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Trafficking protein particle complex subunit 11 (TRAPPC11).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Trafficking protein particle complex subunit 11 (TRAPPC11).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Trafficking protein particle complex subunit 11 (TRAPPC11).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Trafficking protein particle complex subunit 11 (TRAPPC11).	[13]

References

• [1] 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.
• [2] Mutations in TRAPPC11 are associated with a congenital disorder of glycosylation.Hum Mutat. 2017 Feb;38(2):148-151. doi: 10.1002/humu.23145. Epub 2016 Nov 26.
• [3] Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability. Am J Hum Genet. 2013 Jul 11;93(1):181-90. doi: 10.1016/j.ajhg.2013.05.028. Epub 2013 Jul 3.
• [4] TRAPPC11 and GOSR2 mutations associate with hypoglycosylation of -dystroglycan and muscular dystrophy.Skelet Muscle. 2018 May 31;8(1):17. doi: 10.1186/s13395-018-0163-0.
• [5] A novel TRAPPC11 mutation in two Turkish families associated with cerebral atrophy, global retardation, scoliosis, achalasia and alacrima. J Med Genet. 2017 Mar;54(3):176-185. doi: 10.1136/jmedgenet-2016-104108. Epub 2016 Oct 5.
• [6] Genome-wide association study identifies three novel susceptibility loci for systemic lupus erythematosus in Han Chinese.Br J Dermatol. 2018 Aug;179(2):506-508. doi: 10.1111/bjd.16500. Epub 2018 May 23.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.