Details of Drug Off-Target (DOT)

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

• DOT Name: Pendrin (SLC26A4)
• Synonyms: Sodium-independent chloride/iodide transporter; Solute carrier family 26 member 4
• Gene Name: SLC26A4
• Related Disease:
  Autosomal recessive nonsyndromic hearing loss 4
  Pendred syndrome
  Athyreosis
  Hearing loss, autosomal recessive
  Thyroid hypoplasia
• UniProt ID: S26A4_HUMAN
• Pfam ID: PF01740 ; PF00916
• Sequence:
  MAAPGGRSEPPQLPEYSCSYMVSRPVYSELAFQQQHERRLQERKTLRESLAKCCSCSRKR
  AFGVLKTLVPILEWLPKYRVKEWLLSDVISGVSTGLVATLQGMAYALLAAVPVGYGLYSA
  FFPILTYFIFGTSRHISVGPFPVVSLMVGSVVLSMAPDEHFLVSSSNGTVLNTTMIDTAA
  RDTARVLIASALTLLVGIIQLIFGGLQIGFIVRYLADPLVGGFTTAAAFQVLVSQLKIVL
  NVSTKNYNGVLSIIYTLVEIFQNIGDTNLADFTAGLLTIVVCMAVKELNDRFRHKIPVPI
  PIEVIVTIIATAISYGANLEKNYNAGIVKSIPRGFLPPELPPVSLFSEMLAASFSIAVVA
  YAIAVSVGKVYATKYDYTIDGNQEFIAFGISNIFSGFFSCFVATTALSRTAVQESTGGKT
  QVAGIISAAIVMIAILALGKLLEPLQKSVLAAVVIANLKGMFMQLCDIPRLWRQNKIDAV
  IWVFTCIVSIILGLDLGLLAGLIFGLLTVVLRVQFPSWNGLGSIPSTDIYKSTKNYKNIE
  EPQGVKILRFSSPIFYGNVDGFKKCIKSTVGFDAIRVYNKRLKALRKIQKLIKSGQLRAT
  KNGIISDAVSTNNAFEPDEDIEDLEELDIPTKEIEIQVDWNSELPVKVNVPKVPIHSLVL
  DCGAISFLDVVGVRSLRVIVKEFQRIDVNVYFASLQDYVIEKLEQCGFFDDNIRKDTFFL
  TVHDAILYLQNQVKSQEGQGSILETITLIQDCKDTLELIETELTEEELDVQDEAMRTLAS
• Function: Sodium-independent transporter of chloride and iodide. Mediates electroneutral chloride-bicarbonate, chloride-iodide and chloride-formate exchange with 1:1 stoichiometry. Mediates electroneutral iodide-bicarbonate exchange.
• Tissue Specificity: Highly expressed in the kidney (at protein level) . High expression in adult thyroid, lower expression in adult and fetal kidney and fetal brain. Not expressed in other tissues .
• KEGG Pathway: Thyroid hormone synthesis (hsa04918)
• Reactome Pathway:
  Defective SLC26A4 causes Pendred syndrome (PDS) (R-HSA-5619046)
  Multifunctional anion exchangers (R-HSA-427601)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive nonsyndromic hearing loss 4	DISCJIDF	Definitive	Autosomal recessive	[1]
Pendred syndrome	DISZ1MU8	Definitive	Autosomal recessive	[2]
Athyreosis	DISBHHCU	Supportive	Autosomal dominant	[3]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[4]
Thyroid hypoplasia	DISJG17B	Supportive	Autosomal dominant	[3]

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chloride	DM1TJXA	Phase 3	Pendrin (SLC26A4) increases the transport of Chloride.	[11]
Formic Acid	DMNFZC6	Investigative	Pendrin (SLC26A4) increases the transport of Formic Acid.	[12]
IODIDE	DM3FZ6P	Investigative	Pendrin (SLC26A4) affects the transport of IODIDE.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pendrin (SLC26A4).	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Pendrin (SLC26A4).	[6]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Pendrin (SLC26A4).	[7]
Epanova	DMHEAGL	Approved	Epanova increases the expression of Pendrin (SLC26A4).	[8]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone decreases the expression of Pendrin (SLC26A4).	[9]

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 Pendrin (SLC26A4).	[10]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [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] Identification of PENDRIN (SLC26A4) mutations in patients with congenital hypothyroidism and "apparent" thyroid dysgenesis. J Clin Endocrinol Metab. 2014 Jan;99(1):E169-76. doi: 10.1210/jc.2013-2619. Epub 2013 Dec 20.
• [4] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. 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.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [7] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [8] Differential effects of omega-3 and omega-6 Fatty acids on gene expression in breast cancer cells. Breast Cancer Res Treat. 2007 Jan;101(1):7-16. doi: 10.1007/s10549-006-9269-x. Epub 2006 Jul 6.
• [9] Amiodarone reversibly decreases sodium-iodide symporter mRNA expression at therapeutic concentrations and induces antioxidant responses at supraphysiological concentrations in cultured human thyroid follicles. Thyroid. 2007 Dec;17(12):1189-200. doi: 10.1089/thy.2007.0215.
• [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] Functional characterization of pendrin mutations found in the Israeli and Palestinian populations. Cell Physiol Biochem. 2011;28(3):477-84. doi: 10.1159/000335109. Epub 2011 Nov 18.
• [12] Human pendrin expressed in Xenopus laevis oocytes mediates chloride/formate exchange. Am J Physiol Cell Physiol. 2000 Jan;278(1):C207-11. doi: 10.1152/ajpcell.2000.278.1.C207.
• [13] Identification of allelic variants of pendrin (SLC26A4) with loss and gain of function. Cell Physiol Biochem. 2011;28(3):467-76. doi: 10.1159/000335108. Epub 2011 Nov 18.