Pendrin Explained

Pendrin is an anion exchange protein that in humans is encoded by the SLC26A4 gene (solute carrier family 26, member 4).^{[1] [2]} Pendrin was initially identified as a sodium-independent chloride-iodide exchanger^[3] with subsequent studies showing that it also accepts formate and bicarbonate as substrates.^{[4] [5]} 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.^[6]

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.^[7]

Thyroid

In the thyroid, pendrin is expressed by thyroid follicular cells. Na⁺/I⁻ symporter imports iodide (I^-) into the cell across its basolateral side, and pendrin extrudes the I⁻ across the cell's apical membrane into the thyroid colloid.^[8]

Inner ear

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^{[9] [10]} or indirectly modulate the calcium concentration of the endolymph.^[11] 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.^{[12] [13]}

Kidney

Renal β-intercalated cells of the late distal tube and collecting duct express pendrin upon their apical membrane, resorbing one Cl⁻ in exchange for secreting a HCO3⁻, with Cl⁻ subsequently extruded from the cell by a basolateral Cl⁻ channel. β-intercalated cells thus utilise pendrin to contribute to acid-base homeostasis by excreting base (HCO3⁻) into urine. Additionally, β-intercalated cells may use pendrin in concert with a Na⁺/HCO3⁻/2Cl⁻ antiporter in order to resorb NaCl.^[14]

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.^[15] 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.^[1]

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,^{[16] [17]} and overexpression of pendrin results in airway inflammation, hyperreactivity, and increased mucus production.^{[18] [19]} These symptoms could result from pendrin's effects on ion concentration in the airway surface liquid, possibly causing the liquid to be less hydrated.^[20]

Further reading

• Markovich D . Physiological roles and regulation of mammalian sulfate transporters . Physiological Reviews . 81 . 4 . 1499–1533 . October 2001 . 11581495 . 10.1152/physrev.2001.81.4.1499 . 30942862 .
• Baldwin CT, Weiss S, Farrer LA, De Stefano AL, Adair R, Franklyn B, Kidd KK, Korostishevsky M, Bonné-Tamir B . 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 . 1637–1642 . September 1995 . 8541853 . 10.1093/hmg/4.9.1637 .
• Coyle B, Coffey R, Armour JA, Gausden E, Hochberg Z, Grossman A, Britton K, Pembrey M, Reardon W, Trembath R . Pendred syndrome (goitre and sensorineural hearing loss) maps to chromosome 7 in the region containing the nonsyndromic deafness gene DFNB4 . Nature Genetics . 12 . 4 . 421–423 . April 1996 . 8630497 . 10.1038/ng0496-421 . 7166946 .
• Sheffield VC, Kraiem Z, Beck JC, Nishimura D, Stone EM, Salameh M, Sadeh O, Glaser B . Pendred syndrome maps to chromosome 7q21-34 and is caused by an intrinsic defect in thyroid iodine organification . Nature Genetics . 12 . 4 . 424–426 . April 1996 . 8630498 . 10.1038/ng0496-424 . 25888014 .
• Gausden E, Armour JA, Coyle B, Coffey R, Hochberg Z, Pembrey M, Britton KE, Grossman A, Reardon W, Trembath R . Thyroid peroxidase: evidence for disease gene exclusion in Pendred's syndrome . Clinical Endocrinology . 44 . 4 . 441–446 . April 1996 . 8706311 . 10.1046/j.1365-2265.1996.714536.x . 21410631 .
• 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 . 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 . February 1997 . 9070918 . 10.1006/geno.1996.4541 . free . 2066/25039 .
• Li XC, Everett LA, Lalwani AK, Desmukh D, Friedman TB, Green ED, Wilcox ER . A mutation in PDS causes non-syndromic recessive deafness . Nature Genetics . 18 . 3 . 215–217 . March 1998 . 9500541 . 10.1038/ng0398-215 . 40830620 .
• 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 . Two frequent missense mutations in Pendred syndrome . Human Molecular Genetics . 7 . 7 . 1099–1104 . July 1998 . 9618166 . 10.1093/hmg/7.7.1099 . free .
• 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 . Molecular analysis of the PDS gene in Pendred syndrome . Human Molecular Genetics . 7 . 7 . 1105–1112 . July 1998 . 9618167 . 10.1093/hmg/7.7.1105 . free .
• Usami S, Abe S, Weston MD, Shinkawa H, Van Camp G, Kimberling WJ . Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations . Human Genetics . 104 . 2 . 188–192 . February 1999 . 10190331 . 10.1007/s004390050933 . 3116063 .
• Masmoudi S, Charfedine I, Hmani M, Grati M, Ghorbel AM, Elgaied-Boulila A, Drira M, Hardelin JP, Ayadi H . Pendred syndrome: phenotypic variability in two families carrying the same PDS missense mutation . American Journal of Medical Genetics . 90 . 1 . 38–44 . January 2000 . 10602116 . 10.1002/(SICI)1096-8628(20000103)90:1<38::AID-AJMG8>3.0.CO;2-R .
• Reardon W, OMahoney CF, Trembath R, Jan H, Phelps PD . Enlarged vestibular aqueduct: a radiological marker of pendred syndrome, and mutation of the PDS gene . QJM . 93 . 2 . 99–104 . February 2000 . 10700480 . 10.1093/qjmed/93.2.99 . free .
• Bogazzi F, Raggi F, Ultimieri F, Campomori A, Cosci C, Berrettini S, Neri E, La Rocca R, Ronca G, Martino E, Bartalena L . A novel mutation in the pendrin gene associated with Pendred's syndrome . Clinical Endocrinology . 52 . 3 . 279–285 . March 2000 . 10718825 . 10.1046/j.1365-2265.2000.00930.x . 40121366 .
• Bidart JM, Mian C, Lazar V, Russo D, Filetti S, Caillou B, Schlumberger M . Expression of pendrin and the Pendred syndrome (PDS) gene in human thyroid tissues . The Journal of Clinical Endocrinology and Metabolism . 85 . 5 . 2028–2033 . May 2000 . 10843192 . 10.1210/jcem.85.5.6519 . free .
• Adato A, Raskin L, Petit C, Bonne-Tamir B . 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 . 437–442 . June 2000 . 10878664 . 10.1038/sj.ejhg.5200489 . free .
• Lohi H, Kujala M, Kerkelä E, Saarialho-Kere U, Kestilä M, Kere J . Mapping of five new putative anion transporter genes in human and characterization of SLC26A6, a candidate gene for pancreatic anion exchanger . Genomics . 70 . 1 . 102–112 . November 2000 . 11087667 . 10.1006/geno.2000.6355 .
• Campbell C, Cucci RA, Prasad S, Green GE, Edeal JB, Galer CE, Karniski LP, Sheffield VC, Smith RJ . Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations . Human Mutation . 17 . 5 . 403–411 . May 2001 . 11317356 . 10.1002/humu.1116 . 36643824 .

External links

• GeneReviews/NCBI/NIH/UW entry on Pendred Syndrome/DFNB4
• Description at oto.wustl.edu

Notes and References

1. Web site: Entrez Gene: SLC26A4 solute carrier family 26, member 4.
2. Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, Adawi F, Hazani E, Nassir E, Baxevanis AD, Sheffield VC, Green ED . Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS) . Nature Genetics . 17 . 4 . 411–422 . December 1997 . 9398842 . 10.1038/ng1297-411 . 39359838 .
3. Scott DA, Wang R, Kreman TM, Sheffield VC, Karniski LP . The Pendred syndrome gene encodes a chloride-iodide transport protein . Nature Genetics . 21 . 4 . 440–443 . April 1999 . 10192399 . 10.1038/7783 . 23717390 .
4. Scott DA, Karniski LP . Human pendrin expressed in Xenopus laevis oocytes mediates chloride/formate exchange . American Journal of Physiology. Cell Physiology . 278 . 1 . C207–C211 . January 2000 . 10644529 . 10.1152/ajpcell.2000.278.1.c207 . 18841371 . free .
5. Soleimani M, Greeley T, Petrovic S, Wang Z, Amlal H, Kopp P, Burnham CE . Pendrin: an apical Cl-/OH-/HCO3- exchanger in the kidney cortex . American Journal of Physiology. Renal Physiology . 280 . 2 . F356–F364 . February 2001 . 11208611 . 10.1152/ajprenal.2001.280.2.f356 .
6. Book: Patterson C, Runge MS . Principles of molecular medicine . Humana Press . Totowa, NJ . 2006 . 1-58829-202-9 . 957 .
7. Bizhanova A, Kopp P . Controversies concerning the role of pendrin as an apical iodide transporter in thyroid follicular cells . Cellular Physiology and Biochemistry . 28 . 3 . 485–490 . 2011-01-01 . 22116361 . 10.1159/000335103 . free .
8. Kessler J, Obinger C, Eales G . Factors influencing the study of peroxidase-generated iodine species and implications for thyroglobulin synthesis . Thyroid . 18 . 7 . 769–774 . July 2008 . 18631006 . 10.1089/thy.2007.0310 .
9. Karniski LP, Aronson PS . 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 . 6362–6365 . September 1985 . 3862136 . 391054 . 10.1073/pnas.82.18.6362 . free . 1985PNAS...82.6362K .
10. Kim HM, Wangemann P . 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 . November 2010 . 21103348 . 2984494 . 10.1371/journal.pone.0014041 . free . 2010PLoSO...514041K .
11. Wangemann P, Nakaya K, Wu T, Maganti RJ, Itza EM, Sanneman JD, Harbidge DG, Billings S, Marcus DC . 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–F1353 . May 2007 . 17299139 . 2020516 . 10.1152/ajprenal.00487.2006 .
12. Book: Wall SM . The Renal Physiology of Pendrin (SLC26A4) and Its Role in Hypertension . Epithelial Anion Transport in Health and Disease: The Role of the SLC26 Transporters Family . 273 . 231–9; discussion 239–43, 261–4 . 2006 . 17120771 . 10.1002/0470029579.ch15 . 978-0-470-02957-2 . Novartis Foundation Symposia .
13. Royaux IE, Wall SM, Karniski LP, Everett LA, Suzuki K, Knepper MA, Green ED . 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 . 4221–4226 . March 2001 . 11274445 . 31206 . 10.1073/pnas.071516798 . free . 2001PNAS...98.4221R .
14. Book: Berne & Levy Physiology . Elsevier . 2024 . 978-0-323-84790-2 . Koeppen BM, Stanton BA, Swiatecka-Urban A . 8th . Philadelphia, PA .
15. Pela I, Bigozzi M, Bianchi B . Profound hypokalemia and hypochloremic metabolic alkalosis during thiazide therapy in a child with Pendred syndrome . Clinical Nephrology . 69 . 6 . 450–453 . June 2008 . 18538122 . 10.5414/cnp69450 .
16. Kuperman DA, Lewis CC, Woodruff PG, Rodriguez MW, Yang YH, Dolganov GM, Fahy JV, Erle DJ . Dissecting asthma using focused transgenic modeling and functional genomics . The Journal of Allergy and Clinical Immunology . 116 . 2 . 305–311 . August 2005 . 16083784 . 10.1016/j.jaci.2005.03.024 .
17. Zhen G, Park SW, Nguyenvu LT, Rodriguez MW, Barbeau R, Paquet AC, Erle DJ . 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 . 244–253 . February 2007 . 16980555 . 1899314 . 10.1165/rcmb.2006-0180OC .
18. Pedemonte N, Caci E, Sondo E, Caputo A, Rhoden K, Pfeffer U, Di Candia M, Bandettini R, Ravazzolo R, Zegarra-Moran O, Galietta LJ . Thiocyanate transport in resting and IL-4-stimulated human bronchial epithelial cells: role of pendrin and anion channels . Journal of Immunology . 178 . 8 . 5144–5153 . April 2007 . 17404297 . 10.4049/jimmunol.178.8.5144 . free .
19. 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 . Identification of pendrin as a common mediator for mucus production in bronchial asthma and chronic obstructive pulmonary disease . Journal of Immunology . 180 . 9 . 6262–6269 . May 2008 . 18424749 . 10.4049/jimmunol.180.9.6262 . free .
20. Nakagami Y, Favoreto S, Zhen G, Park SW, Nguyenvu LT, Kuperman DA, Dolganov GM, Huang X, Boushey HA, Avila PC, Erle DJ . 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 . 2203–2210 . August 2008 . 18641360 . 2491716 . 10.4049/jimmunol.181.3.2203 .