Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO6H3YF)

• DOT Name: Nebulin-related-anchoring protein (NRAP)
• Synonyms: N-RAP
• Gene Name: NRAP
• Related Disease:
  Nemaline myopathy
  Hypertrophic cardiomyopathy
  Myofibrillar myopathy
  Dilated cardiomyopathy
• UniProt ID: NRAP_HUMAN
• Pfam ID: PF00412 ; PF00880
• Sequence:
  MNVQPCSRCGYGVYPAEKISCIDQIWHKACFHCEVCKMMLSVNNFVSHQKKPYCHAHNPK
  NNTFTSVYHTPLNLNVRTFPEAISGIHDQEDGEQCKSVFHWDMKSKDKEGAPNRQPLANE
  RAYWTGYGEGNAWCPGALPDPEIVRMVEARKSLGEEYTEDYEQPRGKGSFPAMITPAYQR
  AKKANQLASQVEYKRGHDERISRFSTVVDTPELLRSKAGAQLQSDVRYTEDYEQQRGKGS
  FPAMITPAYQIAKRANELASDVRYHQQYQKEMRGMAGPAIGAEGILTRECADQYGQGYPE
  EYEEHRGKGSFPAMITPAYQNAKKAHELASDIKYRQDFNKMKGAAHYHSLPAQDNLVLKQ
  AQSVNKLVSEVEYKKDLESSRGHSINYCETPQFRNVSKISKFTSDNKYKENYQNHMRGRY
  EGVGMDRRTLHAMKVGSLASNVAYKADYKHDIVDYNYPATLTPSYQTAMKLVPLKDANYR
  QSIDKLKYSSVTDTPQIVQAKINAQQLSHVNYRADYEKNKLNYTLPQDVPQLVKAKTNAK
  LFSEVKYKEGWEKTKGKGFEMKLDAMSLLAAKASGELASNIKYKEEYEKTKGKAMGTADS
  RLLHSLQIAKMSSEVEYKKGFEESKTRFHLPMDMVNIRHAKKAQTLASDLDYRKKLHEYT
  VLPEDMKTQWAKKAYGLQSELQYKADLAWMKGVGWLTEGSLNLEQAKKAGQLVSEKNYRQ
  RVDELKFTSVTDSSQMEHAKKSQELQSGVAYKAGNEQSVHQYTISKDEPLFLQARANAAN
  LSEKLYKSSWENQKAKGFELRLDSLTFLAAKAKRDLASEVKYKEDYERSRGKLIGAKDVQ
  GDSQMSHSLQMSKLQSELEYKKGFEDTKSQCHVSLDMVHLVHARKAQHLATDVGYKTAEH
  HFTALPTDMKVEWAKKAYGLQSDNQYRADVKWMKGMGWVATGSLNVEQAKKAGELISEKK
  YRQHPDALKFTSIKDTPEMVQARISYTQAVDRLYREQGENIKHHYTPTADLPEVLLAKLN
  AMNISETRYKESWSKLRDGGYKLRLDALPFQAAKASGEIISDYKYKEAFEKMKGQMLGSR
  SLEDDISLAHSVYATSLQSDVNYKKGFEHSKAQFHLPLDMAALVHAKKAQTLASNQDYKH
  PLPQYTSLAEDLRLSCAKKAHKLQSENLYRSDLNFMRGVACVIPGTLEIEGRKKASELIS
  ESKYRQHPHSFKYTAVTDTPNLLHAKFSNQITNERLYKAAGEDARHEYTMTLGLPEFIRA
  KTNAANLSDARYKESWRNLRAQGYKLTIEALPFQAARASGDIASDFLYRHDFVKERGKLI
  GPQSVRDDPRIQHCRRMGQLQSELQYRRGATSSQAQFHLPMDMVHLVHAKNAQALASDHD
  YRTQYHKFTALPEDLKMAWAKKAHALQSELRYKSDLIGMKGIGWLALRSPQMESAKKAGE
  LISETKYRKKPDSIKFTTVVDSPDLVHAKNSYMHCNERMYRSGDAESLHRYTLIPDHPDF
  TRARLNALHLSDKVYRNSWEQTRAGSYDFRLDAIPFQTARASREIASDFRYKEAFLRDRG
  LQIGYRSVDDDPRMKHFLNVGRLQSDNEYKKDFAKSRSQFHSSTDQPGLLQAKRSQQLAS
  DVHYRQPLPQPTCDPEQLGLRHAQKAHQLQSDVKYKSDLNLTRGVGWTPPGSYKVEMARR
  AAELANARGLGLQGAYRGAEAVEAGDHQSGEVNPDATEILHVKKKKALLL
• Function: May be involved in anchoring the terminal actin filaments in the myofibril to the membrane and in transmitting tension from the myofibrils to the extracellular matrix.
• Tissue Specificity: Expressed in cardiac and skeletal muscle.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nemaline myopathy	DIS5IYLY	Definitive	Biomarker	[1]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[2]
Myofibrillar myopathy	DISF24LW	Strong	Genetic Variation	[3]
Dilated cardiomyopathy	DISX608J	Disputed	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nebulin-related-anchoring protein (NRAP).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Nebulin-related-anchoring protein (NRAP).	[6]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Nebulin-related-anchoring protein (NRAP).	[7]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Nebulin-related-anchoring protein (NRAP).	[8]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Nebulin-related-anchoring protein (NRAP).	[5]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Nebulin-related-anchoring protein (NRAP).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Nebulin-related-anchoring protein (NRAP).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nebulin-related-anchoring protein (NRAP).	[10]

References

• [1] Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in nemaline myopathy.Hum Mol Genet. 2019 Aug 1;28(15):2549-2560. doi: 10.1093/hmg/ddz078.
• [2] Decreased interactions of mutant muscle LIM protein (MLP) with N-RAP and alpha-actinin and their implication for hypertrophic cardiomyopathy.Cell Tissue Res. 2004 Aug;317(2):129-36. doi: 10.1007/s00441-004-0873-y. Epub 2004 Jun 16.
• [3] Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy.J Muscle Res Cell Motil. 2016 Jun;37(3):101-15. doi: 10.1007/s10974-016-9451-7. Epub 2016 Jul 21.
• [4] Homozygous truncating mutation in NRAP gene identified by whole exome sequencing in a patient with dilated cardiomyopathy.Sci Rep. 2017 Jun 13;7(1):3362. doi: 10.1038/s41598-017-03189-8.
• [5] Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016 Nov;90(11):2763-2777.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [8] Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch Toxicol. 2018 Apr;92(4):1507-1524.
• [9] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [10] 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.