Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAJAVP9)

• DOT Name: Spectrin beta chain, non-erythrocytic 4 (SPTBN4)
• Synonyms: Beta-IV spectrin; Spectrin, non-erythroid beta chain 3
• Gene Name: SPTBN4
• Related Disease:
  Neurodevelopmental disorder with hypotonia, neuropathy, and deafness
  Non-insulin dependent diabetes
  Cardiovascular disease
  Clear cell renal carcinoma
  Congenital fiber-type disproportion myopathy
  Congenital myopathy
  Myopathy
  Papillary renal cell carcinoma
  Polycystic ovarian syndrome
  Renal cell carcinoma
  Auditory neuropathy
• UniProt ID: SPTN4_HUMAN
• Pfam ID: PF00307 ; PF15410 ; PF00435
• Sequence:
  MAQVPGEVDNMEGLPAPNNNPAARWESPDRGWEREQPAASTAAASLFECSRIKALADERE
  AVQKKTFTKWVNSHLARVGCHIGDLYVDLRDGFVLTRLLEVLSGEQLPRPTRGRMRIHSL
  ENVDKALQFLKEQRVHLENVGSHDIVDGNHRLTLGLVWTIILRFQIQVIKIETEDNRETR
  SAKDALLLWCQMKTAGYPEVNIQNFTTSWRDGLAFNALIHRHRPDLVDFSKLTKSNANYN
  LQRAFRTAEQHLGLARLLDPEDVNMEAPDEKSIITYVVSFYHYFSKMKALAVEGKRIGKV
  LDQVLEVGKIIERYEELAAELLAWIHRTVGLISNQKFANSLSGVQQQLQAFTAYCTLEKP
  VKFQEKGNLEVLLFSIQSKLRACNRRLFVPREGCGIWDIDKAWGELEKAEHEREAALRAE
  LIRQEKLELLAQRFDHKVAMRESWLNENQRLVSQDNFGYELPAVEAAMKKHEAIEADIAA
  YEERVQGVAELAQALAAEGYYDIRRVAAQRDSVLRQWALLTGLVGARRTRLEQNLALQKV
  FQEMVYMVDWMEEMQAQLLSRECGQHLVEADDLLQKHGLLEGDIAAQSERVEALNAAALR
  FSQLQGYQPCDPQVICNRVNHVHGCLAELQEQAARRRAELEASRSLWALLQELEEAESWA
  RDKERLLEAAGGGGAAGAAGAAGTAGGAHDLSSTARLLAQHKILQGELGGRRALLQQALR
  CGEELVAAGGAVGPGADTVHLVGLAERAASARRRWQRLEEAAARRERRLQEARALHQFGA
  DLDGLLDWLRDAYRLAAAGDFGHDEASSRRLARQHRALTGEVEAHRGPVSGLRRQLATLG
  GASGAGPLVVALQVRVVEAEQLFAEVTEVAALRRQWLRDALAVYRMFGEVHACELWIGEK
  EQWLLSMRVPDSLDDVEVVQHRFESLDQEMNSLMGRVLDVNHTVQELVEGGHPSSDEVRS
  CQDHLNSRWNRIVELVEQRKEEMSAVLLVENHVLEVAEVRAQVREKRRAVESAPRAGGAL
  QWRLSGLEAALQALEPRQAALLEEAALLAERFPAQAARLHQGAEELGAEWGALASAAQAC
  GEAVAAAGRLQRFLHDLDAFLDWLVRAQEAAGGSEGPLPNSLEEADALLARHAALKEEVD
  QREEDYARIVAASEALLAADGAELGPGLALDEWLPHLELGWHKLLGLWEARREALVQAHI
  YQLFLRDLRQALVVLRNQEMALSGAELPGTVESVEEALKQHRDFLTTMELSQQKMQVAVQ
  AAEGLLRQGNIYGEQAQEAVTRLLEKNQENQLRAQQWMQKLHDQLELQHFLRDCHELDGW
  IHEKMLMARDGTREDNHKLHKRWLRHQAFMAELAQNKEWLEKIEREGQQLMQEKPELAAS
  VRKKLGEIRQCWAELESTTQAKARQLFEASKADQLVQSFAELDKKLLHMESQLQDVDPGG
  DLATVNSQLKKLQSMESQVEEWYREVGELQAQTAALPLEPASKELVGERQNAVGERLVRL
  LEPLQERRRLLLASKELHQVAHDLDDELAWVQERLPLAMQTERGNGLQAVQQHIKKNQGL
  RREIQAHGPRLEEVLERAGALASLRSPEAEAVRRGLEQLQSAWAGLREAAERRQQVLDAA
  FQVEQYYFDVAEVEAWLGEQELLMMSEDKGKDEQSTLQLLKKHLQLEQGVENYEESIAQL
  SRQCRALLEMGHPDSEQISRRQSQVDRLYVALKELGEERRVALEQQYWLYQLSRQVSELE
  HWIAEKEVVAGSPELGQDFEHVSVLQEKFSEFASETGMAGRERLAAVNQMVDELIECGHT
  AAATMAEWKDGLNEAWAELLELMGTRAQLLAASRELHKFFSDARELQGQIEEKRRRLPRL
  TTPPEPRPSASSMQRTLRAFEHDLQLLVSQVRQLQEGAAQLRTVYAGEHAEAIASREQEV
  LQGWKELLSACEDARLHVSSTADALRFHSQVRDLLSWMDGIASQIGAADKPRDVSSVEVL
  MNYHQGLKTELEARVPELTTCQELGRSLLLNKSAMADEIQAQLDKLGTRKEEVSEKWDRH
  WEWLQQMLEVHQFAQEAVVADAWLTAQEPLLQSRELGSSVDEVEQLIRRHEAFRKAAAAW
  EERFSSLRRLTTIEKIKAEQSKQPPTPLLGRKFFGDPTELAAKAAPLLRPGGYERGLEPL
  ARRASDTLSAEVRTRVGYVRQELKPERLQPRIDRLPEIPGRVEPAALPAAPEDAAETPAT
  PAAAEQVRPRPERQESADRAEELPRRRRPERQESVDQSEEAARRRRPERQESAEHEAAHS
  LTLGRYEQMERRRERRERRLERQESSEQEMPIRGDLVKGKATLADIVEQLQEKEAGPGLP
  AGPSLPQPRELPPGRLPNGLELPERTPRPDRPRARDRPKPRRRPRPREGGEGGGSRRSRS
  APAQGGSAPAPPPPPTHTVQHEGFLLRKRELDANRKSSNRSWVSLYCVLSKGELGFYKDS
  KGPASGSTHGGEPLLSLHKATSEVASDYKKKKHVFKLQTQDGSEFLLQAKDEEEMNGWLE
  AVASSVAEHAEIARWGQTLPTTSSTDEGNPKREGGDRRASGRRK
• Tissue Specificity: Expressed in skeletal muscle at the sarcolemma and in the muscle capillaries (at protein level) . Abundantly expressed in brain and pancreatic islets .
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway:
  Interaction between L1 and Ankyrins (R-HSA-445095)
  RAF/MAP kinase cascade (R-HSA-5673001)
  COPI-mediated anterograde transport (R-HSA-6807878)
  NCAM signaling for neurite out-growth (R-HSA-375165)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with hypotonia, neuropathy, and deafness	DISZ34OT	Definitive	Autosomal recessive	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[2]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[4]
Congenital fiber-type disproportion myopathy	DISU9T2M	Strong	Biomarker	[5]
Congenital myopathy	DISLSK9G	Strong	Genetic Variation	[5]
Myopathy	DISOWG27	Strong	Biomarker	[5]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[4]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[4]
Auditory neuropathy	DISM6GAU	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Spectrin beta chain, non-erythrocytic 4 (SPTBN4).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Spectrin beta chain, non-erythrocytic 4 (SPTBN4).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Spectrin beta chain, non-erythrocytic 4 (SPTBN4).	[11]

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 Spectrin beta chain, non-erythrocytic 4 (SPTBN4).	[10]

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] Type 2 Diabetes Leads to Axon Initial Segment Shortening in db/db Mice.Front Cell Neurosci. 2018 Jun 8;12:146. doi: 10.3389/fncel.2018.00146. eCollection 2018.
• [3] IV-Spectrin/STAT3 complex regulates fibroblast phenotype, fibrosis, and cardiac function.JCI Insight. 2019 Oct 17;4(20):e131046. doi: 10.1172/jci.insight.131046.
• [4] Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma.Nat Genet. 2011 Dec 4;44(1):17-9. doi: 10.1038/ng.1014.
• [5] A recessive mutation in beta-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness.Hum Genet. 2017 Jul;136(7):903-910. doi: 10.1007/s00439-017-1814-7. Epub 2017 May 24.
• [6] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [7] Reorganization of Destabilized Nodes of Ranvier in IV Spectrin Mutants Uncovers Critical Timelines for Nodal Restoration and Prevention of Motor Paresis.J Neurosci. 2018 Jul 11;38(28):6267-6282. doi: 10.1523/JNEUROSCI.0515-18.2018. Epub 2018 Jun 15.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [10] 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.
• [11] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.