Skip to main content

Advertisement

SpringerLink
Log in

Pathophysiological aspects of the thick ascending limb and novel genetic defects: HELIX syndrome and transient antenatal Bartter syndrome

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

The thick ascending limb plays a central role in human kidney physiology, participating in sodium reabsorption, urine concentrating mechanisms, calcium and magnesium homeostasis, bicarbonate and ammonium homeostasis, and uromodulin synthesis. This review aims to illustrate the importance of these roles from a pathophysiological point of view by describing the interactions of the key proteins of this segment and by discussing how recently identified and long-known hereditary diseases affect this segment. The descriptions of two recently described salt-losing tubulopathies, transient antenatal Bartter syndrome and HELIX syndrome, which are caused by mutations in MAGED2 and CLDN10 genes, respectively, highlight the role of new players in the modulation of sodium reabsorption the thick ascending limb.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Mount DB (2014) Thick ascending limb of the loop of Henle. Clin J Am Soc Nephrol 9:1974–1986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bankir L, Figueres L, Prot-Bertoye C, Bouby N, Crambert G, Pratt JH, Houillier P (2020) Medullary and cortical thick ascending limb: similarities and differences. Am J Physiol Ren Physiol 318:F422–F442

    Article  CAS  Google Scholar 

  3. Bazua-Valenti S, Castaneda-Bueno M, Gamba G (2016) Physiological role of SLC12 family members in the kidney. Am J Physiol Ren Physiol 311:F131–F144

    Article  CAS  Google Scholar 

  4. Welling PA, Ho K (2009) A comprehensive guide to the ROMK potassium channel: form and function in health and disease. Am J Physiol Ren Physiol 297:F849–F863

    Article  CAS  Google Scholar 

  5. Fahlke C, Fischer M (2010) Physiology and pathophysiology of ClC-K/barttin channels. Front Physiol 1:155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Castrop H, Schnermann J (2008) Isoforms of renal Na-K-2Cl cotransporter NKCC2: expression and functional significance. Am J Physiol Ren Physiol 295:F859–F866

    Article  CAS  Google Scholar 

  7. Carota I, Theilig F, Oppermann M, Kongsuphol P, Rosenauer A, Schreiber R, Jensen BL, Walter S, Kunzelmann K, Castrop H (2010) Localization and functional characterization of the human NKCC2 isoforms. Acta Physiol (Oxford) 199:327–338

    CAS  Google Scholar 

  8. Fenton RA, Poulsen SB, de la Mora Chavez S, Soleimani M, Dominguez Rieg JA, Rieg T (2017) Renal tubular NHE3 is required in the maintenance of water and sodium chloride homeostasis. Kidney Int 92:397–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tsukita S, Tanaka H, Tamura A (2019) The claudins: from tight junctions to biological systems. Trends Biochem Sci 44:141–152

    Article  CAS  PubMed  Google Scholar 

  10. Gong Y, Hou J (2017) Claudins in barrier and transport function-the kidney. Pflugers Arch 469:105–113

    Article  CAS  PubMed  Google Scholar 

  11. Muto S (2017) Physiological roles of claudins in kidney tubule paracellular transport. Am J Physiol Ren Physiol 312:F9–F24

    Article  CAS  Google Scholar 

  12. Prot-Bertoye C, Houillier P (2020) Claudins in renal physiology and pathology. Genes (Basel) 11:290

    Article  CAS  Google Scholar 

  13. Milatz S, Breiderhoff T (2017) One gene, two paracellular ion channels-claudin-10 in the kidney. Pflugers Arch 469:115–121

    Article  CAS  PubMed  Google Scholar 

  14. Plain A, Wulfmeyer VC, Milatz S, Klietz A, Hou J, Bleich M, Himmerkus N (2016) Corticomedullary difference in the effects of dietary Ca(2)(+) on tight junction properties in thick ascending limbs of Henle's loop. Pflugers Arch 468:293–303

    Article  CAS  PubMed  Google Scholar 

  15. Simon DB, Karet FE, Hamdan JM, DiPietro A, Sanjad SA, Lifton RP (1996) Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet 13:183–198

    Article  CAS  PubMed  Google Scholar 

  16. Vargas-Poussou R, Feldmann D, Vollmer M, Konrad M, Kelly L, van den Heuvel LP, Tebourbi L, Brandis M, Karolyi L, Hebert SC, Lemmink HH, Deschenes G, Hildebrandt F, Seyberth HW, Guay-Woodford LM, Knoers NV, Antignac C (1998) Novel molecular variants of the Na-K-2Cl cotransporter gene are responsible for antenatal Bartter syndrome. Am J Hum Genet 62:1332–1340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Simon DB, Karet FE, Rodriguez-Soriano J, Hamdan JH, DiPietro A, Trachtman H, Sanjad SA, Lifton RP (1996) Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 14:152–156

    Article  CAS  PubMed  Google Scholar 

  18. Simon DB, Bindra RS, Mansfield TA, Nelson-Williams C, Mendonca E, Stone R, Schurman S, Nayir A, Alpay H, Bakkaloglu A, Rodriguez-Soriano J, Morales JM, Sanjad SA, Taylor CM, Pilz D, Brem A, Trachtman H, Griswold W, Richard GA, John E, Lifton RP (1997) Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nat Genet 17:171–178

    Article  CAS  PubMed  Google Scholar 

  19. Seys E, Andrini O, Keck M, Mansour-Hendili L, Courand PY, Simian C, Deschenes G, Kwon T, Bertholet-Thomas A, Bobrie G, Borde JS, Bourdat-Michel G, Decramer S, Cailliez M, Krug P, Cozette P, Delbet JD, Dubourg L, Chaveau D, Fila M, Jourde-Chiche N, Knebelmann B, Lavocat MP, Lemoine S, Djeddi D, Llanas B, Louillet F, Merieau E, Mileva M, Mota-Vieira L, Mousson C, Nobili F, Novo R, Roussey-Kesler G, Vrillon I, Walsh SB, Teulon J, Blanchard A, Vargas-Poussou R (2017) Clinical and genetic spectrum of Bartter syndrome type 3. J Am Soc Nephrol 28:2540–2552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Birkenhager R, Otto E, Schurmann MJ, Vollmer M, Ruf EM, Maier-Lutz I, Beekmann F, Fekete A, Omran H, Feldmann D, Milford DV, Jeck N, Konrad M, Landau D, Knoers NV, Antignac C, Sudbrak R, Kispert A, Hildebrandt F (2001) Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nat Genet 29:310–314

    Article  CAS  PubMed  Google Scholar 

  21. Schlingmann KP, Konrad M, Jeck N, Waldegger P, Reinalter SC, Holder M, Seyberth HW, Waldegger S (2004) Salt wasting and deafness resulting from mutations in two chloride channels. N Engl J Med 350:1314–1319

    Article  CAS  PubMed  Google Scholar 

  22. Laghmani K, Beck BB, Yang SS, Seaayfan E, Wenzel A, Reusch B, Vitzthum H, Priem D, Demaretz S, Bergmann K, Duin LK, Gobel H, Mache C, Thiele H, Bartram MP, Dombret C, Altmuller J, Nurnberg P, Benzing T, Levtchenko E, Seyberth HW, Klaus G, Yigit G, Lin SH, Timmer A, de Koning TJ, Scherjon SA, Schlingmann KP, Bertrand MJ, Rinschen MM, de Backer O, Konrad M, Komhoff M (2016) Polyhydramnios, transient antenatal Bartter's syndrome, and MAGED2 mutations. N Engl J Med 374:1853–1863

    Article  CAS  PubMed  Google Scholar 

  23. Bongers E, Shelton LM, Milatz S, Verkaart S, Bech AP, Schoots J, Cornelissen EAM, Bleich M, Hoenderop JGJ, Wetzels JFM, Lugtenberg D, Nijenhuis T (2017) A novel hypokalemic-alkalotic salt-losing tubulopathy in patients with CLDN10 mutations. J Am Soc Nephrol 28:3118–3128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hadj-Rabia S, Brideau G, Al-Sarraj Y, Maroun RC, Figueres ML, Leclerc-Mercier S, Olinger E, Baron S, Chaussain C, Nochy D, Taha RZ, Knebelmann B, Joshi V, Curmi PA, Kambouris M, Vargas-Poussou R, Bodemer C, Devuyst O, Houillier P, El-Shanti H (2018) Multiplex epithelium dysfunction due to CLDN10 mutation: the HELIX syndrome. Genet Med 20:190–201

    Article  CAS  PubMed  Google Scholar 

  25. Klar J, Piontek J, Milatz S, Tariq M, Jameel M, Breiderhoff T, Schuster J, Fatima A, Asif M, Sher M, Mabert K, Fromm A, Baig SM, Gunzel D, Dahl N (2017) Altered paracellular cation permeability due to a rare CLDN10B variant causes anhidrosis and kidney damage. PLoS Genet 13:e1006897

    Article  PubMed  PubMed Central  Google Scholar 

  26. Hou J, Renigunta A, Konrad M, Gomes AS, Schneeberger EE, Paul DL, Waldegger S, Goodenough DA (2008) Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex. J Clin Invest 118:619–628

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Gong Y, Renigunta V, Himmerkus N, Zhang J, Renigunta A, Bleich M, Hou J (2012) Claudin-14 regulates renal Ca(+)(+) transport in response to CaSR signalling via a novel microRNA pathway. EMBO J 31:1999–2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dimke H, Desai P, Borovac J, Lau A, Pan W, Alexander RT (2013) Activation of the Ca(2+)-sensing receptor increases renal claudin-14 expression and urinary Ca(2+) excretion. Am J Physiol Ren Physiol 304:F761–F769

    Article  CAS  Google Scholar 

  29. Gong Y, Hou J (2014) Claudin-14 underlies Ca(+)(+)-sensing receptor-mediated Ca(+)(+) metabolism via NFAT-microRNA-based mechanisms. J Am Soc Nephrol 25:745–760

    Article  CAS  PubMed  Google Scholar 

  30. Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D, Milford D, Sanjad S, Lifton RP (1999) Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 285:103–106

    Article  CAS  PubMed  Google Scholar 

  31. Konrad M, Schaller A, Seelow D, Pandey AV, Waldegger S, Lesslauer A, Vitzthum H, Suzuki Y, Luk JM, Becker C, Schlingmann KP, Schmid M, Rodriguez-Soriano J, Ariceta G, Cano F, Enriquez R, Juppner H, Bakkaloglu SA, Hediger MA, Gallati S, Neuhauss SC, Nurnberg P, Weber S (2006) Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. Am J Hum Genet 79:949–957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bardet C, Courson F, Wu Y, Khaddam M, Salmon B, Ribes S, Thumfart J, Yamaguti PM, Rochefort GY, Figueres ML, Breiderhoff T, Garcia-Castano A, Vallee B, Le Denmat D, Baroukh B, Guilbert T, Schmitt A, Masse JM, Bazin D, Lorenz G, Morawietz M, Hou J, Carvalho-Lobato P, Manzanares MC, Fricain JC, Talmud D, Demontis R, Neves F, Zenaty D, Berdal A, Kiesow A, Petzold M, Menashi S, Linglart A, Acevedo AC, Vargas-Poussou R, Muller D, Houillier P, Chaussain C (2016) Claudin-16 deficiency impairs tight junction function in ameloblasts, leading to abnormal enamel formation. J Bone Miner Res 31:498–513

    Article  CAS  PubMed  Google Scholar 

  33. Yamaguti PM, Neves FA, Hotton D, Bardet C, de La Dure-Molla M, Castro LC, Scher MD, Barbosa ME, Ditsch C, Fricain JC, de La Faille R, Figueres ML, Vargas-Poussou R, Houillier P, Chaussain C, Babajko S, Berdal A, Acevedo AC (2017) Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis caused by CLDN19 gene mutations. J Med Genet 54:26–37

    Article  CAS  PubMed  Google Scholar 

  34. Hannan FM, Babinsky VN, Thakker RV (2016) Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis. J Mol Endocrinol 57:R127–R142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Watanabe S, Fukumoto S, Chang H, Takeuchi Y, Hasegawa Y, Okazaki R, Chikatsu N, Fujita T (2002) Association between activating mutations of calcium-sensing receptor and Bartter's syndrome. Lancet 360:692–694

    Article  CAS  PubMed  Google Scholar 

  36. Vargas-Poussou R, Huang C, Hulin P, Houillier P, Jeunemaitre X, Paillard M, Planelles G, Dechaux M, Miller RT, Antignac C (2002) Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome. J Am Soc Nephrol 13:2259–2266

    Article  CAS  PubMed  Google Scholar 

  37. Thorleifsson G, Holm H, Edvardsson V, Walters GB, Styrkarsdottir U, Gudbjartsson DF, Sulem P, Halldorsson BV, de Vegt F, d'Ancona FC, den Heijer M, Franzson L, Christiansen C, Alexandersen P, Rafnar T, Kristjansson K, Sigurdsson G, Kiemeney LA, Bodvarsson M, Indridason OS, Palsson R, Kong A, Thorsteinsdottir U, Stefansson K (2009) Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density. Nat Genet 41:926–930

    Article  CAS  PubMed  Google Scholar 

  38. Guha M, Bankura B, Ghosh S, Pattanayak AK, Ghosh S, Pal DK, Puri A, Kundu AK, Das M (2015) Polymorphisms in CaSR and CLDN14 genes associated with increased risk of kidney stone disease in patients from the eastern part of India. PLoS One 10:e0130790

    Article  PubMed  PubMed Central  Google Scholar 

  39. Corre T, Olinger E, Harris SE, Traglia M, Ulivi S, Lenarduzzi S, Belge H, Youhanna S, Tokonami N, Bonny O, Houillier P, Polasek O, Deary IJ, Starr JM, Toniolo D, Gasparini P, Vollenweider P, Hayward C, Bochud M, Devuyst O (2017) Common variants in CLDN14 are associated with differential excretion of magnesium over calcium in urine. Pflugers Arch 469:91–103

    Article  CAS  PubMed  Google Scholar 

  40. Good DW (1993) The thick ascending limb as a site of renal bicarbonate reabsorption. Semin Nephrol 13:225–235

    CAS  PubMed  Google Scholar 

  41. Wang T, Hropot M, Aronson PS, Giebisch G (2001) Role of NHE isoforms in mediating bicarbonate reabsorption along the nephron. Am J Physiol Ren Physiol 281:F1117–F1122

    Article  CAS  Google Scholar 

  42. Weiner ID, Verlander JW (2017) Ammonia transporters and their role in acid-base balance. Physiol Rev 97:465–494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hart TC, Gorry MC, Hart PS, Woodard AS, Shihabi Z, Sandhu J, Shirts B, Xu L, Zhu H, Barmada MM, Bleyer AJ (2002) Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet 39:882–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Devuyst O, Olinger E, Rampoldi L (2017) Uromodulin: from physiology to rare and complex kidney disorders. Nat Rev Nephrol 13:525–544

    Article  CAS  PubMed  Google Scholar 

  45. Mutig K, Kahl T, Saritas T, Godes M, Persson P, Bates J, Raffi H, Rampoldi L, Uchida S, Hille C, Dosche C, Kumar S, Castaneda-Bueno M, Gamba G, Bachmann S (2011) Activation of the bumetanide-sensitive Na+,K+,2Cl- cotransporter (NKCC2) is facilitated by Tamm–Horsfall protein in a chloride-sensitive manner. J Biol Chem 286:30200–30210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Renigunta A, Renigunta V, Saritas T, Decher N, Mutig K, Waldegger S (2011) Tamm–Horsfall glycoprotein interacts with renal outer medullary potassium channel ROMK2 and regulates its function. J Biol Chem 286:2224–2235

    Article  CAS  PubMed  Google Scholar 

  47. Bachmann S, Mutig K, Bates J, Welker P, Geist B, Gross V, Luft FC, Alenina N, Bader M, Thiele BJ, Prasadan K, Raffi HS, Kumar S (2005) Renal effects of Tamm–Horsfall protein (uromodulin) deficiency in mice. Am J Physiol Ren Physiol 288:F559–F567

    Article  CAS  Google Scholar 

  48. Graham LA, Padmanabhan S, Fraser NJ, Kumar S, Bates JM, Raffi HS, Welsh P, Beattie W, Hao S, Leh S, Hultstrom M, Ferreri NR, Dominiczak AF, Graham D, McBride MW (2014) Validation of uromodulin as a candidate gene for human essential hypertension. Hypertension 63:551–558

    Article  CAS  PubMed  Google Scholar 

  49. Devuyst O, Olinger E, Weber S, Eckardt KU, Kmoch S, Rampoldi L, Bleyer AJ (2019) Autosomal dominant tubulointerstitial kidney disease. Nat Rev Dis Primers 5:60

    Article  PubMed  Google Scholar 

  50. Legrand A, Treard C, Roncelin I, Dreux S, Bertholet-Thomas A, Broux F, Bruno D, Decramer S, Deschenes G, Djeddi D, Guigonis V, Jay N, Khalifeh T, Llanas B, Morin D, Morin G, Nobili F, Pietrement C, Ryckewaert A, Salomon R, Vrillon I, Blanchard A, Vargas-Poussou R (2018) Prevalence of novel MAGED2 mutations in antenatal Bartter syndrome. Clin J Am Soc Nephrol 13:242–250

    Article  PubMed  Google Scholar 

  51. Arthuis CJ, Nizon M, Komhoff M, Beck BB, Riehmer V, Bihouee T, Bruel A, Benbrik N, Winer N, Isidor B (2018) A step towards precision medicine in management of severe transient polyhydramnios: MAGED2 variant. J Obstet Gynaecol 39:395–397

    Article  PubMed  Google Scholar 

  52. Meyer M, Berrios M, Lo C (2018) Transient antenatal Bartter's syndrome: a case report. Front Pediatr 6:51

    Article  PubMed  PubMed Central  Google Scholar 

  53. Florke Gee RR, Chen H, Lee AK, Daly CA, Wilander BA, Fon Tacer K, Potts PR (2020) Emerging roles of the MAGE protein family in stress response pathways. J Biol Chem 295:16121–16155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Limbutara K, Chou CL, Knepper MA (2020) Quantitative proteomics of all 14 renal tubule segments in rat. J Am Soc Nephrol 31:1255–1266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Valino-Rivas L, Cuarental L, Agustin M, Husi H, Cannata-Ortiz P, Sanz AB, Mischak H, Ortiz A, Sanchez-Nino MD (2019) MAGE genes in the kidney: identification of MAGED2 as upregulated during kidney injury and in stressed tubular cells. Nephrol Dial Transplant 34:1498–1507

    Article  CAS  PubMed  Google Scholar 

  56. Breiderhoff T, Himmerkus N, Stuiver M, Mutig K, Will C, Meij IC, Bachmann S, Bleich M, Willnow TE, Muller D (2012) Deletion of claudin-10 (Cldn10) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis. Proc Natl Acad Sci U S A 109:14241–14246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Van Itallie CM, Rogan S, Yu A, Vidal LS, Holmes J, Anderson JM (2006) Two splice variants of claudin-10 in the kidney create paracellular pores with different ion selectivities. Am J Physiol Ren Physiol 291:F1288–F1299

    Article  Google Scholar 

  58. Gunzel D, Stuiver M, Kausalya PJ, Haisch L, Krug SM, Rosenthal R, Meij IC, Hunziker W, Fromm M, Muller D (2009) Claudin-10 exists in six alternatively spliced isoforms that exhibit distinct localization and function. J Cell Sci 122:1507–1517

    Article  PubMed  Google Scholar 

  59. Inai T, Sengoku A, Guan X, Hirose E, Iida H, Shibata Y (2005) Heterogeneity in expression and subcellular localization of tight junction proteins, claudin-10 and -15, examined by RT-PCR and immunofluorescence microscopy. Arch Histol Cytol 68:349–360

    Article  CAS  PubMed  Google Scholar 

  60. Meyers N, Nelson-Williams C, Malaga-Dieguez L, Kaufmann H, Loring E, Knight J, Lifton RP, Trachtman H (2019) Hypokalemia associated with a claudin 10 mutation: a case report. Am J Kidney Dis 73:425–428

    Article  PubMed  Google Scholar 

  61. Milatz S (2019) A novel claudinopathy based on claudin-10 mutations. Int J Mol Sci 20:5396

    Article  CAS  PubMed Central  Google Scholar 

  62. Breiderhoff T, Himmerkus N, Drewell H, Plain A, Gunzel D, Mutig K, Willnow TE, Muller D, Bleich M (2018) Deletion of claudin-10 rescues claudin-16-deficient mice from hypomagnesemia and hypercalciuria. Kidney Int 93:580–588

    Article  CAS  PubMed  Google Scholar 

  63. Hong JH, Park S, Shcheynikov N, Muallem S (2013) Mechanism and synergism in epithelial fluid and electrolyte secretion. Pflugers Arch 466:1487–1499

    Article  PubMed  PubMed Central  Google Scholar 

  64. Pedersen AML, Sorensen CE, Proctor GB, Carpenter GH, Ekstrom J (2018) Salivary secretion in health and disease. J Oral Rehabil 45:730–746

    Article  CAS  PubMed  Google Scholar 

  65. Baker OJ (2016) Current trends in salivary gland tight junctions. Tissue Barriers 4:e1162348

    Article  PubMed  PubMed Central  Google Scholar 

  66. Cui CY, Schlessinger D (2015) Eccrine sweat gland development and sweat secretion. Exp Dermatol 24:644–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Delporte C (2009) Aquaporins in secretory glands and their role in Sjogren's syndrome. Handb Exp Pharmacol 190:185–201

    Article  CAS  Google Scholar 

  68. Sato T, Courbebaisse M, Ide N, Fan Y, Hanai JI, Kaludjerovic J, Densmore MJ, Yuan Q, Toka HR, Pollak MR, Hou J, Lanske B (2017) Parathyroid hormone controls paracellular Ca(2+) transport in the thick ascending limb by regulating the tight-junction protein Claudin14. Proc Natl Acad Sci U S A 114:E3344–E3353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kompatscher A, de Baaij JHF, Aboudehen K, Farahani S, van Son LHJ, Milatz S, Himmerkus N, Veenstra GC, Bindels RJM, Hoenderop JGJ (2018) Transcription factor HNF1beta regulates expression of the calcium-sensing receptor in the thick ascending limb of the kidney. Am J Physiol Ren Physiol 315:F27–F35

    Article  CAS  Google Scholar 

  70. Tokonami N, Olinger E, Debaix H, Houillier P, Devuyst O (2018) The excretion of uromodulin is modulated by the calcium-sensing receptor. Kidney Int 94:882–886

    Article  CAS  PubMed  Google Scholar 

  71. Hou J, Renigunta V, Nie M, Sunq A, Himmerkus N, Quintanova C, Bleich M, Renigunta A, Wolf MTF (2019) Phosphorylated claudin-16 interacts with Trpv5 and regulates transcellular calcium transport in the kidney. Proc Natl Acad Sci U S A 116:19176–19186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Muller D, Kausalya PJ, Claverie-Martin F, Meij IC, Eggert P, Garcia-Nieto V, Hunziker W (2003) A novel claudin 16 mutation associated with childhood hypercalciuria abolishes binding to ZO-1 and results in lysosomal mistargeting. Am J Hum Genet 73:1293–1301

    Article  PubMed  PubMed Central  Google Scholar 

  73. Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, Tobin J, Lieberer E, Sterner C, Landoure G, Arora R, Sirimanna T, Thompson D, Cross JH, van't Hoff W, Al Masri O, Tullus K, Yeung S, Anikster Y, Klootwijk E, Hubank M, Dillon MJ, Heitzmann D, Arcos-Burgos M, Knepper MA, Dobbie A, Gahl WA, Warth R, Sheridan E, Kleta R (2009) Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med 360:1960–1970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Scholl UI, Choi M, Liu T, Ramaekers VT, Hausler MG, Grimmer J, Tobe SW, Farhi A, Nelson-Williams C, Lifton RP (2009) Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. Proc Natl Acad Sci U S A 106:5842–5847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhang C, Wang L, Su XT, Lin DH, Wang WH (2015) KCNJ10 (Kir4.1) is expressed in the basolateral membrane of the cortical thick ascending limb. Am J Physiol Ren Physiol 308:F1288–F1296

    Article  CAS  Google Scholar 

  76. de Baaij JH, Dorresteijn EM, Hennekam EA, Kamsteeg EJ, Meijer R, Dahan K, Muller M, van den Dorpel MA, Bindels RJ, Hoenderop JG, Devuyst O, Knoers NV (2015) Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia. Nephrol Dial Transplant 30:952–957

    Article  PubMed  Google Scholar 

  77. Schlingmann KP, Bandulik S, Mammen C, Tarailo-Graovac M, Holm R, Baumann M, Konig J, Lee JJY, Drogemoller B, Imminger K, Beck BB, Altmuller J, Thiele H, Waldegger S, Van't Hoff W, Kleta R, Warth R, van Karnebeek CDM, Vilsen B, Bockenhauer D, Konrad M (2018) Germline de novo mutations in ATP1A1 cause renal hypomagnesemia, refractory seizures, and intellectual disability. Am J Hum Genet 103:808–816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Konrad M, Hou J, Weber S, Dotsch J, Kari JA, Seeman T, Kuwertz-Broking E, Peco-Antic A, Tasic V, Dittrich K, Alshaya HO, von Vigier RO, Gallati S, Goodenough DA, Schaller A (2008) CLDN16 genotype predicts renal decline in familial hypomagnesemia with hypercalciuria and nephrocalcinosis. J Am Soc Nephrol 19:171–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Godron A, Harambat J, Boccio V, Mensire A, May A, Rigothier C, Couzi L, Barrou B, Godin M, Chauveau D, Faguer S, Vallet M, Cochat P, Eckart P, Guest G, Guigonis V, Houillier P, Blanchard A, Jeunemaitre X, Vargas-Poussou R (2012) Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype–genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations. Clin J Am Soc Nephrol 7:801–809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Olinger E, Hofmann P, Kidd K, Dufour I, Belge H, Schaeffer C, Kipp A, Bonny O, Deltas C, Demoulin N, Fehr T, Fuster DG, Gale DP, Goffin E, Hodanova K, Huynh-Do U, Kistler A, Morelle J, Papagregoriou G, Pirson Y, Sandford R, Sayer JA, Torra R, Venzin C, Venzin R, Vogt B, Zivna M, Greka A, Dahan K, Rampoldi L, Kmoch S, Bleyer AJ Sr, Devuyst O (2020) Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1. Kidney Int 98:717–731

    Article  CAS  PubMed  Google Scholar 

  81. Pearce SH, Williamson C, Kifor O, Bai M, Coulthard MG, Davies M, Lewis-Barned N, McCredie D, Powell H, Kendall-Taylor P, Brown EM, Thakker RV (1996) A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N Engl J Med 335:1115–1122

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Genetics, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, 20-40 rue Leblanc, 75015, Paris, France

    Rosa Vargas-Poussou

  2. Centre de Référence des Maladies Rénales Héréditaires de l’Enfant et de l’Adulte (MARHEA), Paris, France

    Rosa Vargas-Poussou

  3. Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France

    Rosa Vargas-Poussou

Authors
  1. Rosa Vargas-Poussou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rosa Vargas-Poussou.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vargas-Poussou, R. Pathophysiological aspects of the thick ascending limb and novel genetic defects: HELIX syndrome and transient antenatal Bartter syndrome. Pediatr Nephrol 37, 239–252 (2022). https://doi.org/10.1007/s00467-021-05019-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-021-05019-6

Keywords

Search

Navigation