Pendrin

Pendrin, is an anion exchange protein that in humans is encoded by the SLC26A4 gene (solute carrier family 26, member 4).[5][6] Pendrin was initially identified as a sodium-independent chloride-iodide exchanger[7] with subsequent studies showing that it also accepts formate and bicarbonate as substrates.[8][9] Pendrin is similar to the Band 3 transport protein found in red blood cells. Pendrin is the protein which is mutated in Pendred syndrome, which is an autosomal recessive disorder characterized by sensorineural hearing loss, goiter and a partial organification problem detectable by a positive perchlorate test.[10]

SLC26A4
Identifiers
AliasesSLC26A4, DFNB4, EVA, PDS, TDH2B, solute carrier family 26 member 4
External IDsOMIM: 605646 MGI: 1346029 HomoloGene: 20132 GeneCards: SLC26A4
Gene location (Human)
Chr.Chromosome 7 (human)[1]
Band7q22.3Start107,660,828 bp[1]
End107,717,809 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

5172

23985

Ensembl

ENSG00000091137

ENSMUSG00000020651

UniProt

O43511

Q9R155

RefSeq (mRNA)

NM_000441

NM_011867

RefSeq (protein)

NP_000432

NP_035997

Location (UCSC)Chr 7: 107.66 – 107.72 MbChr 12: 31.52 – 31.56 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Pendrin is responsible for mediating the electroneutral exchange of chloride (Cl−) for bicarbonate (HCO3−) across a plasma membrane in the chloride cells of freshwater fish.

By phylogenetic analysis, pendrin has been found to be a close relative of prestin present on the hair cells or organ of corti in the inner ear. Prestin is primarily an electromechanical transducer but pendrin is an ion transporter.

Function

Pendrin is an ion exchanger found in many types of cells in the body. High levels of pendrin expression have been identified in the inner ear and thyroid. In the thyroid, pendrin mediates a component of the efflux of iodide across the apical membrane of the thyrocyte, which is critical for the formation of thyroid hormone.[11] The exact function of pendrin in the inner ear remains unclear; however, pendrin may play a role in acid-base balance as a chloride-bicarbonate exchanger, regulate volume homeostasis through its ability to function as a chloride-formate exchanger[12][13] or indirectly modulate the calcium concentration of the endolymph.[14] Pendrin is also expressed in the kidney, and has been localized to the apical membrane of a population of intercalated cells in the cortical collecting duct where it is involved in bicarbonate secretion.[15][16]

Thyroid hormone synthesis, with Pendrin seen at center between the follicular colloid and the follicular cell.

Clinical significance

Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. Pendred syndrome is characterized by thyroid goiter and enlargement of the vestibular aqueduct resulting in deafness; however, despite being expressed in the kidney, individuals with Pendred syndrome do not show any kidney-related acid-base, or volume abnormalities under basal conditions. This is probably the result of other bicarbonate or chloride transporters in the kidney compensating for any loss of pendrin function. Only under extreme situations of salt depletion or metabolic alkalosis, or with inactivation of the sodium-chloride cotransporter, are fluid and electrolyte disorders manifested in these patients.[17] SLC26A4 is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters.[5]

Another little-understood role of pendrin is in airway hyperreactivity and inflammation, as during asthma attacks and allergic reactions. Expression of pendrin in the lung increases in response to allergens and high concentrations of IL-13,[18][19] and overexpression of pendrin results in airway inflammation, hyperreactivity, and increased mucus production.[20][21] These symptoms could result from pendrin's effects on ion concentration in the airway surface liquid, possibly causing the liquid to be less hydrated.[22]

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gollark: https://dragcave.net/images/tOTh.png
gollark: Oops, that's the same dragon.
gollark: https://dragcave.net/images/tOTh.png vs https://dragcave.net/images/tOTh.png
gollark: For all the talk of how nebulae each have unique patterns, their patterns look *really* similar.

References
  1. GRCh38: Ensembl release 89: ENSG00000091137 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000020651 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: SLC26A4 solute carrier family 26, member 4".
  6. Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, Adawi F, Hazani E, Nassir E, Baxevanis AD, Sheffield VC, Green ED (December 1997). "Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS)". Nature Genetics. 17 (4): 411–22. doi:10.1038/ng1297-411. PMID 9398842.
  7. Scott DA, Wang R, Kreman TM, Sheffield VC, Karniski LP (April 1999). "The Pendred syndrome gene encodes a chloride-iodide transport protein". Nature Genetics. 21 (4): 440–3. doi:10.1038/7783. PMID 10192399.
  8. Scott DA, Karniski LP (January 2000). "Human pendrin expressed in Xenopus laevis oocytes mediates chloride/formate exchange". American Journal of Physiology. Cell Physiology. 278 (1): C207-11. doi:10.1152/ajpcell.2000.278.1.c207. PMID 10644529.
  9. Soleimani M, Greeley T, Petrovic S, Wang Z, Amlal H, Kopp P, Burnham CE (February 2001). "Pendrin: an apical Cl-/OH-/HCO3- exchanger in the kidney cortex". American Journal of Physiology. Renal Physiology. 280 (2): F356-64. doi:10.1152/ajprenal.2001.280.2.f356. PMID 11208611.
  10. Patterson C, Runge MS (2006). Principles of molecular medicine. Totowa, NJ: Humana Press. p. 957. ISBN 1-58829-202-9.
  11. Bizhanova A, Kopp P (2011-01-01). "Controversies concerning the role of pendrin as an apical iodide transporter in thyroid follicular cells". Cellular Physiology and Biochemistry. 28 (3): 485–90. doi:10.1159/000335103. PMID 22116361.
  12. Karniski LP, Aronson PS (September 1985). "Chloride/formate exchange with formic acid recycling: a mechanism of active chloride transport across epithelial membranes". Proceedings of the National Academy of Sciences of the United States of America. 82 (18): 6362–5. doi:10.1073/pnas.82.18.6362. PMC 391054. PMID 3862136.
  13. Kim HM, Wangemann P (November 2010). "Failure of fluid absorption in the endolymphatic sac initiates cochlear enlargement that leads to deafness in mice lacking pendrin expression". PLOS ONE. 5 (11): e14041. doi:10.1371/journal.pone.0014041. PMC 2984494. PMID 21103348.
  14. Wangemann P, Nakaya K, Wu T, Maganti RJ, Itza EM, Sanneman JD, Harbidge DG, Billings S, Marcus DC (May 2007). "Loss of cochlear HCO3- secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model". American Journal of Physiology. Renal Physiology. 292 (5): F1345-53. doi:10.1152/ajprenal.00487.2006. PMC 2020516. PMID 17299139.
  15. Wall SM (2006). "The renal physiology of pendrin (SLC26A4) and its role in hypertension". Novartis Foundation Symposium. Novartis Foundation Symposia. 273: 231–9, discussion 239–43, 261–4. doi:10.1002/0470029579.ch15. ISBN 978-0-470-02957-2. PMID 17120771.
  16. Royaux IE, Wall SM, Karniski LP, Everett LA, Suzuki K, Knepper MA, Green ED (March 2001). "Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion". Proceedings of the National Academy of Sciences of the United States of America. 98 (7): 4221–6. doi:10.1073/pnas.071516798. PMC 31206. PMID 11274445.
  17. Pela I, Bigozzi M, Bianchi B (June 2008). "Profound hypokalemia and hypochloremic metabolic alkalosis during thiazide therapy in a child with Pendred syndrome". Clinical Nephrology. 69 (6): 450–3. doi:10.5414/cnp69450. PMID 18538122.
  18. Kuperman DA, Lewis CC, Woodruff PG, Rodriguez MW, Yang YH, Dolganov GM, Fahy JV, Erle DJ (August 2005). "Dissecting asthma using focused transgenic modeling and functional genomics". The Journal of Allergy and Clinical Immunology. 116 (2): 305–11. doi:10.1016/j.jaci.2005.03.024. PMID 16083784.
  19. Zhen G, Park SW, Nguyenvu LT, Rodriguez MW, Barbeau R, Paquet AC, Erle DJ (February 2007). "IL-13 and epidermal growth factor receptor have critical but distinct roles in epithelial cell mucin production". American Journal of Respiratory Cell and Molecular Biology. 36 (2): 244–53. doi:10.1165/rcmb.2006-0180OC. PMC 1899314. PMID 16980555.
  20. Pedemonte N, Caci E, Sondo E, Caputo A, Rhoden K, Pfeffer U, Di Candia M, Bandettini R, Ravazzolo R, Zegarra-Moran O, Galietta LJ (April 2007). "Thiocyanate transport in resting and IL-4-stimulated human bronchial epithelial cells: role of pendrin and anion channels". Journal of Immunology. 178 (8): 5144–53. doi:10.4049/jimmunol.178.8.5144. PMID 17404297.
  21. Nakao I, Kanaji S, Ohta S, Matsushita H, Arima K, Yuyama N, Yamaya M, Nakayama K, Kubo H, Watanabe M, Sagara H, Sugiyama K, Tanaka H, Toda S, Hayashi H, Inoue H, Hoshino T, Shiraki A, Inoue M, Suzuki K, Aizawa H, Okinami S, Nagai H, Hasegawa M, Fukuda T, Green ED, Izuhara K (May 2008). "Identification of pendrin as a common mediator for mucus production in bronchial asthma and chronic obstructive pulmonary disease". Journal of Immunology. 180 (9): 6262–9. doi:10.4049/jimmunol.180.9.6262. PMID 18424749.
  22. Nakagami Y, Favoreto S, Zhen G, Park SW, Nguyenvu LT, Kuperman DA, Dolganov GM, Huang X, Boushey HA, Avila PC, Erle DJ (August 2008). "The epithelial anion transporter pendrin is induced by allergy and rhinovirus infection, regulates airway surface liquid, and increases airway reactivity and inflammation in an asthma model". Journal of Immunology. 181 (3): 2203–10. doi:10.4049/jimmunol.181.3.2203. PMC 2491716. PMID 18641360.

Further reading
  • Markovich D (October 2001). "Physiological roles and regulation of mammalian sulfate transporters". Physiological Reviews. 81 (4): 1499–533. doi:10.1152/physrev.2001.81.4.1499. PMID 11581495.
  • Baldwin CT, Weiss S, Farrer LA, De Stefano AL, Adair R, Franklyn B, Kidd KK, Korostishevsky M, Bonné-Tamir B (September 1995). "Linkage of congenital, recessive deafness (DFNB4) to chromosome 7q31 and evidence for genetic heterogeneity in the Middle Eastern Druze population". Human Molecular Genetics. 4 (9): 1637–42. doi:10.1093/hmg/4.9.1637. PMID 8541853.
  • Coyle B, Coffey R, Armour JA, Gausden E, Hochberg Z, Grossman A, Britton K, Pembrey M, Reardon W, Trembath R (April 1996). "Pendred syndrome (goitre and sensorineural hearing loss) maps to chromosome 7 in the region containing the nonsyndromic deafness gene DFNB4". Nature Genetics. 12 (4): 421–3. doi:10.1038/ng0496-421. PMID 8630497.
  • Sheffield VC, Kraiem Z, Beck JC, Nishimura D, Stone EM, Salameh M, Sadeh O, Glaser B (April 1996). "Pendred syndrome maps to chromosome 7q21-34 and is caused by an intrinsic defect in thyroid iodine organification". Nature Genetics. 12 (4): 424–6. doi:10.1038/ng0496-424. PMID 8630498.
  • Gausden E, Armour JA, Coyle B, Coffey R, Hochberg Z, Pembrey M, Britton KE, Grossman A, Reardon W, Trembath R (April 1996). "Thyroid peroxidase: evidence for disease gene exclusion in Pendred's syndrome". Clinical Endocrinology. 44 (4): 441–6. doi:10.1046/j.1365-2265.1996.714536.x. PMID 8706311.
  • Coucke P, Van Camp G, Demirhan O, Kabakkaya Y, Balemans W, Van Hauwe P, Van Agtmael T, Smith RJ, Parving A, Bolder CH, Cremers CW, Willems PJ (February 1997). "The gene for Pendred syndrome is located between D7S501 and D7S692 in a 1.7-cM region on chromosome 7q". Genomics. 40 (1): 48–54. doi:10.1006/geno.1996.4541. hdl:2066/25039. PMID 9070918.
  • Li XC, Everett LA, Lalwani AK, Desmukh D, Friedman TB, Green ED, Wilcox ER (March 1998). "A mutation in PDS causes non-syndromic recessive deafness". Nature Genetics. 18 (3): 215–7. doi:10.1038/ng0398-215. PMID 9500541.
  • Van Hauwe P, Everett LA, Coucke P, Scott DA, Kraft ML, Ris-Stalpers C, Bolder C, Otten B, de Vijlder JJ, Dietrich NL, Ramesh A, Srisailapathy SC, Parving A, Cremers CW, Willems PJ, Smith RJ, Green ED, Van Camp G (July 1998). "Two frequent missense mutations in Pendred syndrome". Human Molecular Genetics. 7 (7): 1099–104. doi:10.1093/hmg/7.7.1099. PMID 9618166.
  • Coyle B, Reardon W, Herbrick JA, Tsui LC, Gausden E, Lee J, Coffey R, Grueters A, Grossman A, Phelps PD, Luxon L, Kendall-Taylor P, Scherer SW, Trembath RC (July 1998). "Molecular analysis of the PDS gene in Pendred syndrome". Human Molecular Genetics. 7 (7): 1105–12. doi:10.1093/hmg/7.7.1105. PMID 9618167.
  • Usami S, Abe S, Weston MD, Shinkawa H, Van Camp G, Kimberling WJ (February 1999). "Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations". Human Genetics. 104 (2): 188–92. doi:10.1007/s004390050933. PMID 10190331.
  • Masmoudi S, Charfedine I, Hmani M, Grati M, Ghorbel AM, Elgaied-Boulila A, Drira M, Hardelin JP, Ayadi H (January 2000). "Pendred syndrome: phenotypic variability in two families carrying the same PDS missense mutation". American Journal of Medical Genetics. 90 (1): 38–44. doi:10.1002/(SICI)1096-8628(20000103)90:1<38::AID-AJMG8>3.0.CO;2-R. PMID 10602116.
  • Reardon W, OMahoney CF, Trembath R, Jan H, Phelps PD (February 2000). "Enlarged vestibular aqueduct: a radiological marker of pendred syndrome, and mutation of the PDS gene". QJM. 93 (2): 99–104. doi:10.1093/qjmed/93.2.99. PMID 10700480.
  • Bogazzi F, Raggi F, Ultimieri F, Campomori A, Cosci C, Berrettini S, Neri E, La Rocca R, Ronca G, Martino E, Bartalena L (March 2000). "A novel mutation in the pendrin gene associated with Pendred's syndrome". Clinical Endocrinology. 52 (3): 279–85. doi:10.1046/j.1365-2265.2000.00930.x. PMID 10718825.
  • Bidart JM, Mian C, Lazar V, Russo D, Filetti S, Caillou B, Schlumberger M (May 2000). "Expression of pendrin and the Pendred syndrome (PDS) gene in human thyroid tissues". The Journal of Clinical Endocrinology and Metabolism. 85 (5): 2028–33. doi:10.1210/jc.85.5.2028. PMID 10843192.
  • Adato A, Raskin L, Petit C, Bonne-Tamir B (June 2000). "Deafness heterogeneity in a Druze isolate from the Middle East: novel OTOF and PDS mutations, low prevalence of GJB2 35delG mutation and indication for a new DFNB locus". European Journal of Human Genetics. 8 (6): 437–42. doi:10.1038/sj.ejhg.5200489. PMID 10878664.
  • Lohi H, Kujala M, Kerkelä E, Saarialho-Kere U, Kestilä M, Kere J (November 2000). "Mapping of five new putative anion transporter genes in human and characterization of SLC26A6, a candidate gene for pancreatic anion exchanger". Genomics. 70 (1): 102–12. doi:10.1006/geno.2000.6355. PMID 11087667.
  • Campbell C, Cucci RA, Prasad S, Green GE, Edeal JB, Galer CE, Karniski LP, Sheffield VC, Smith RJ (May 2001). "Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations". Human Mutation. 17 (5): 403–11. doi:10.1002/humu.1116. PMID 11317356.
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