Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNSKJU0)

• DOT Name: Dysferlin (DYSF)
• Synonyms: Dystrophy-associated fer-1-like protein; Fer-1-like protein 1
• Gene Name: DYSF
• Related Disease:
  Autosomal recessive limb-girdle muscular dystrophy
  Qualitative or quantitative defects of dysferlin
  Autosomal recessive limb-girdle muscular dystrophy type 2B
  Distal myopathy with anterior tibial onset
  Congenital myopathy, Paradas type
  Miyoshi myopathy
• UniProt ID: DYSF_HUMAN
• PDB ID: 4CAH; 4CAI; 4IHB; 4IQH; 7JOF; 7K6B; 7KRB
• Pfam ID: PF00168 ; PF08165 ; PF08150 ; PF08151 ; PF16165
• Sequence:
  MLRVFILYAENVHTPDTDISDAYCSAVFAGVKKRTKVIKNSVNPVWNEGFEWDLKGIPLD
  QGSELHVVVKDHETMGRNRFLGEAKVPLREVLATPSLSASFNAPLLDTKKQPTGASLVLQ
  VSYTPLPGAVPLFPPPTPLEPSPTLPDLDVVADTGGEEDTEDQGLTGDEAEPFLDQSGGP
  GAPTTPRKLPSRPPPHYPGIKRKRSAPTSRKLLSDKPQDFQIRVQVIEGRQLPGVNIKPV
  VKVTAAGQTKRTRIHKGNSPLFNETLFFNLFDSPGELFDEPIFITVVDSRSLRTDALLGE
  FRMDVGTIYREPRHAYLRKWLLLSDPDDFSAGARGYLKTSLCVLGPGDEAPLERKDPSED
  KEDIESNLLRPTGVALRGAHFCLKVFRAEDLPQMDDAVMDNVKQIFGFESNKKNLVDPFV
  EVSFAGKMLCSKILEKTANPQWNQNITLPAMFPSMCEKMRIRIIDWDRLTHNDIVATTYL
  SMSKISAPGGEIEEEPAGAVKPSKASDLDDYLGFLPTFGPCYINLYGSPREFTGFPDPYT
  ELNTGKGEGVAYRGRLLLSLETKLVEHSEQKVEDLPADDILRVEKYLRRRKYSLFAAFYS
  ATMLQDVDDAIQFEVSIGNYGNKFDMTCLPLASTTQYSRAVFDGCHYYYLPWGNVKPVVV
  LSSYWEDISHRIETQNQLLGIADRLEAGLEQVHLALKAQCSTEDVDSLVAQLTDELIAGC
  SQPLGDIHETPSATHLDQYLYQLRTHHLSQITEAALALKLGHSELPAALEQAEDWLLRLR
  ALAEEPQNSLPDIVIWMLQGDKRVAYQRVPAHQVLFSRRGANYCGKNCGKLQTIFLKYPM
  EKVPGARMPVQIRVKLWFGLSVDEKEFNQFAEGKLSVFAETYENETKLALVGNWGTTGLT
  YPKFSDVTGKIKLPKDSFRPSAGWTWAGDWFVCPEKTLLHDMDAGHLSFVEEVFENQTRL
  PGGQWIYMSDNYTDVNGEKVLPKDDIECPLGWKWEDEEWSTDLNRAVDEQGWEYSITIPP
  ERKPKHWVPAEKMYYTHRRRRWVRLRRRDLSQMEALKRHRQAEAEGEGWEYASLFGWKFH
  LEYRKTDAFRRRRWRRRMEPLEKTGPAAVFALEGALGGVMDDKSEDSMSVSTLSFGVNRP
  TISCIFDYGNRYHLRCYMYQARDLAAMDKDSFSDPYAIVSFLHQSQKTVVVKNTLNPTWD
  QTLIFYEIEIFGEPATVAEQPPSIVVELYDHDTYGADEFMGRCICQPSLERMPRLAWFPL
  TRGSQPSGELLASFELIQREKPAIHHIPGFEVQETSRILDESEDTDLPYPPPQREANIYM
  VPQNIKPALQRTAIEILAWGLRNMKSYQLANISSPSLVVECGGQTVQSCVIRNLRKNPNF
  DICTLFMEVMLPREELYCPPITVKVIDNRQFGRRPVVGQCTIRSLESFLCDPYSAESPSP
  QGGPDDVSLLSPGEDVLIDIDDKEPLIPIQEEEFIDWWSKFFASIGEREKCGSYLEKDFD
  TLKVYDTQLENVEAFEGLSDFCNTFKLYRGKTQEETEDPSVIGEFKGLFKIYPLPEDPAI
  PMPPRQFHQLAAQGPQECLVRIYIVRAFGLQPKDPNGKCDPYIKISIGKKSVSDQDNYIP
  CTLEPVFGKMFELTCTLPLEKDLKITLYDYDLLSKDEKIGETVVDLENRLLSKFGARCGL
  PQTYCVSGPNQWRDQLRPSQLLHLFCQQHRVKAPVYRTDRVMFQDKEYSIEEIEAGRIPN
  PHLGPVEERLALHVLQQQGLVPEHVESRPLYSPLQPDIEQGKLQMWVDLFPKALGRPGPP
  FNITPRRARRFFLRCIIWNTRDVILDDLSLTGEKMSDIYVKGWMIGFEEHKQKTDVHYRS
  LGGEGNFNWRFIFPFDYLPAEQVCTIAKKDAFWRLDKTESKIPARVVFQIWDNDKFSFDD
  FLGSLQLDLNRMPKPAKTAKKCSLDQLDDAFHPEWFVSLFEQKTVKGWWPCVAEEGEKKI
  LAGKLEMTLEIVAESEHEERPAGQGRDEPNMNPKLEDPRRPDTSFLWFTSPYKTMKFILW
  RRFRWAIILFIILFILLLFLAIFIYAFPNYAAMKLVKPFS
• Function: Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion. Plays a role in the sarcolemma repair mechanism of both skeletal muscle and cardiomyocytes that permits rapid resealing of membranes disrupted by mechanical stress.
• Tissue Specificity: Expressed in skeletal muscle, myoblast, myotube and in the syncytiotrophoblast (STB) of the placenta (at protein level). Ubiquitous. Highly expressed in skeletal muscle. Also found in heart, brain, spleen, intestine, placenta and at lower levels in liver, lung, kidney and pancreas.
• Reactome Pathway: Smooth Muscle Contraction (R-HSA-445355)

Molecular Interaction Atlas (MIA) of This DOT

6 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]
Qualitative or quantitative defects of dysferlin	DIS59VEJ	Definitive	Autosomal recessive	[1]
Autosomal recessive limb-girdle muscular dystrophy type 2B	DISWWCL7	Strong	Autosomal recessive	[2]
Distal myopathy with anterior tibial onset	DIS04ZWK	Strong	Autosomal recessive	[3]
Congenital myopathy, Paradas type	DISEYWC0	Supportive	Autosomal recessive	[4]
Miyoshi myopathy	DIS3O1UR	Supportive	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Dysferlin (DYSF).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dysferlin (DYSF).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dysferlin (DYSF).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dysferlin (DYSF).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dysferlin (DYSF).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Dysferlin (DYSF).	[11]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Dysferlin (DYSF).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Dysferlin (DYSF).	[12]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Dysferlin (DYSF).	[13]
Amiloride	DMRTSGP	Approved	Amiloride decreases the expression of Dysferlin (DYSF).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dysferlin (DYSF).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dysferlin (DYSF).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Dysferlin (DYSF).	[17]

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] Dysferlinopathy. 2004 Feb 5 [updated 2021 May 27]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] Phenotypic study in 40 patients with dysferlin gene mutations: high frequency of atypical phenotypes. Arch Neurol. 2007 Aug;64(8):1176-82. doi: 10.1001/archneur.64.8.1176.
• [4] A new phenotype of dysferlinopathy with congenital onset. Neuromuscul Disord. 2009 Jan;19(1):21-5. doi: 10.1016/j.nmd.2008.09.015. Epub 2008 Dec 11.
• [5] Analysis of the DYSF mutational spectrum in a large cohort of patients. Hum Mutat. 2009 Feb;30(2):E345-75. doi: 10.1002/humu.20910.
• [6] 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.
• [7] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [8] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [9] 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.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [14] In vivo and in vitro dysferlin expression in human muscle satellite cells. J Neuropathol Exp Neurol. 2004 Oct;63(10):1104-13. doi: 10.1093/jnen/63.10.1104.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] 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.