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Clinical aspects of the phosphate transporters NaPi-IIa and NaPi-IIb: mutations and disease associations

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Abstract

The Na+-dependent phosphate transporter NaPi-IIa (SLC34A1) is mostly expressed in kidney, whereas NaPi-IIb (SLC34A2) has a wider tissue distribution with prominent expression in the lung and small intestine. NaPi-IIa is involved in renal reabsorption of inorganic phosphate (Pi) from urine, and patients with biallelic inactivating mutations in SLC34A1 develop hypophosphatemia, hypercalcemia, hypercalciuria and nephrocalcinosis, and nephrolithiasis in early childhood. Monoallelic mutations are frequent in the general population and may impact on the risk to develop kidney stones in adulthood. SNPs in close vicinity to the SLC34A1 locus associate with the risk to develop CKD. NaPi-IIb mediates high-affinity transport of Pi from the diet and appears to be mostly important during low Pi availability. Biallelic inactivating SLC34A2 mutations are found in patients with pulmonary alveolar microlithiasis, a lung disease characterized by the deposition of microcrystals. In contrast, no evidence for disturbed systemic Pi homeostasis has been reported in these patients to date. Nevertheless, NaPi-IIb-mediated intestinal Pi absorption may be a target for pharmaceutical interventions in patients with chronic kidney disease and Pi overload.

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References

  1. Albano G, Moor M, Dolder S, Siegrist M, Wagner CA, Biber J, Hernando N, Hofstetter W, Bonny O, Fuster DG (2015) Sodium-dependent phosphate transporters in osteoclast differentiation and function. PLoS One 10:e0125104. https://doi.org/10.1371/journal.pone.0125104

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS (1998) Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci U S A 95:5372–5377

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Bergwitz C, Juppner H (2012) FGF23 and syndromes of abnormal renal phosphate handling. Adv Exp Med Biol 728:41–64. https://doi.org/10.1007/978-1-4614-0887-1_3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Bergwitz C, Miyamoto KI (2018) Hereditary hypophosphatemic rickets with hypercalciuria: pathophysiology, clinical presentation, diagnosis and therapy. Pflugers Arch. https://doi.org/10.1007/s00424-018-2184-2

  5. Biber J, Hernando N, Forster I, Murer H (2009) Regulation of phosphate transport in proximal tubules. Pflugers Arch 458:39–52. https://doi.org/10.1007/s00424-008-0580-8

    Article  PubMed  CAS  Google Scholar 

  6. Block GA, Hulbert-Shearon TE, Levin NW, Port FK (1998) Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 31:607–617

    Article  PubMed  CAS  Google Scholar 

  7. Braun DA, Lawson JA, Gee HY, Halbritter J, Shril S, Tan W, Stein D, Wassner AJ, Ferguson MA, Gucev Z, Fisher B, Spaneas L, Varner J, Sayer JA, Milosevic D, Baum M, Tasic V, Hildebrandt F (2016) Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis. Clin J Am Soc Nephrol 11:664–672. https://doi.org/10.2215/CJN.07540715

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Bricker NS, Morrin PA, Kime SW Jr (1960) The pathologic physiology of chronic Bright’s disease. An exposition of the “intact nephron hypothesis”. Am J Med 28:77–98

    Article  PubMed  CAS  Google Scholar 

  9. Budoff MJ, Rader DJ, Reilly MP, Mohler ER III, Lash J, Yang W, Rosen L, Glenn M, Teal V, Feldman HI (2011) Relationship of estimated GFR and coronary artery calcification in the CRIC (Chronic Renal Insufficiency Cohort) study. Am J Kidney Dis 58:519–526. https://doi.org/10.1053/j.ajkd.2011.04.024

    Article  PubMed  PubMed Central  Google Scholar 

  10. Caballero D, Li Y, Ponsetto J, Zhu C, Bergwitz C (2017) Impaired urinary osteopontin excretion in Npt2a-/- mice. Am J Physiol Renal Physiol 312:F77–F83. https://doi.org/10.1152/ajprenal.00367.2016

    Article  PubMed  CAS  Google Scholar 

  11. Capuano P, Radanovic T, Wagner CA, Bacic D, Kato S, Uchiyama Y, St-Arnoud R, Murer H, Biber J (2005) Intestinal and renal adaptation to a low-Pi diet of type II NaPi cotransporters in vitamin D receptor- and 1alphaOHase-deficient mice. Am J Physiol Cell Physiol 288:C429–C434

    Article  PubMed  CAS  Google Scholar 

  12. Chen H, Xu H, Dong J, Li J, Ghishan FK (2009) Tumor necrosis factor-alpha impairs intestinal phosphate absorption in colitis. Am J Physiol Gastrointest Liver Physiol 296:G775–G781. https://doi.org/10.1152/ajpgi.90722.2008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Christakos S, Veldurthy V, Patel N, Wei R (2017) Intestinal regulation of calcium: vitamin D and bone physiology. Adv Exp Med Biol 1033:3–12. https://doi.org/10.1007/978-3-319-66653-2_1

    Article  PubMed  CAS  Google Scholar 

  14. Clarke BL, Brown EM, Collins MT, Juppner H, Lakatos P, Levine MA, Mannstadt MM, Bilezikian JP, Romanischen AF, Thakker RV (2016) Epidemiology and diagnosis of hypoparathyroidism. J Clin Endocrinol Metab 101:2284–2299. https://doi.org/10.1210/jc.2015-3908

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Corut A, Senyigit A, Ugur SA, Altin S, Ozcelik U, Calisir H, Yildirim Z, Gocmen A, Tolun A (2006) Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am J Hum Genet 79:650–656. https://doi.org/10.1086/508263

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Dandan S, Yuqin C, Wei L, Ziheng P, Dapeng Z, Jianzhu Y, Xin X, Yonghong L, Fengjun T (2018) Novel deletion of SLC34A2 in Chinese patients of PAM shares mutation hot spot with fusion gene SLC34A2-ROS1 in lung cancer. J Genet 97:939–944

    Article  PubMed  CAS  Google Scholar 

  17. Demir K, Yildiz M, Bahat H, Goldman M, Hassan N, Tzur S, Ofir A, Magen D (2017) Clinical heterogeneity and phenotypic expansion of NaPi-IIa-associated disease. J Clin Endocrinol Metab 102:4604–4614. https://doi.org/10.1210/jc.2017-01592

    Article  PubMed  Google Scholar 

  18. Devuyst O, Pattaro C (2018) The UMOD locus: insights into the pathogenesis and prognosis of kidney disease. J Am Soc Nephrol 29:713–726. https://doi.org/10.1681/ASN.2017070716

    Article  PubMed  CAS  Google Scholar 

  19. Dinour D, Davidovits M, Ganon L, Ruminska J, Forster IC, Hernando N, Eyal E, Holtzman EJ, Wagner CA (2016) Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency. Pediatr Nephrol 31:2289–2297. https://doi.org/10.1007/s00467-016-3443-0

    Article  PubMed  Google Scholar 

  20. Dogan OT, Ozsahin SL, Gul E, Arslan S, Koksal B, Berk S, Ozdemir O, Akkurt I (2010) A frame-shift mutation in the SLC34A2 gene in three patients with pulmonary alveolar microlithiasis in an inbred family. Intern Med 49:45–49

    Article  PubMed  CAS  Google Scholar 

  21. Econs MJ (2017) Genetic diseases resulting from disordered FGF23/klotho biology. Bone 100:56–61. https://doi.org/10.1016/j.bone.2016.10.015

    Article  PubMed  CAS  Google Scholar 

  22. Eto N, Miyata Y, Ohno H, Yamashita T (2005) Nicotinamide prevents the development of hyperphosphataemia by suppressing intestinal sodium-dependent phosphate transporter in rats with adenine-induced renal failure. Nephrol Dial Transplant 20:1378–1384. https://doi.org/10.1093/ndt/gfh781

    Article  PubMed  CAS  Google Scholar 

  23. Fearn A, Allison B, Rice SJ, Edwards N, Halbritter J, Bourgeois S, Pastor-Arroyo EM, Hildebrandt F, Tasic V, Wagner CA, Hernando N, Sayer JA, Werner A (2018) Clinical, biochemical, and pathophysiological analysis of SLC34A1 mutations. Physiol Rep 6:e13715. https://doi.org/10.14814/phy2.13715

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Ferreira Francisco FA, Pereira e Silva JL, Hochhegger B, Zanetti G, Marchiori E (2013) Pulmonary alveolar microlithiasis. State-of-the-art review. Respir Med 107:1–9. https://doi.org/10.1016/j.rmed.2012.10.014

    Article  PubMed  Google Scholar 

  25. Forster IC (2018) The molecular mechanism of SLC34 proteins: insights from two decades of transport assays and structure-function studies. Pflugers Arch. https://doi.org/10.1007/s00424-018-2207-z

  26. Fouque D, Vervloet M, Ketteler M (2018) Targeting gastrointestinal transport proteins to control hyperphosphatemia in chronic kidney disease. Drugs 78:1171–1186. https://doi.org/10.1007/s40265-018-0950-2

    Article  PubMed  PubMed Central  Google Scholar 

  27. Giral H, Caldas Y, Sutherland E, Wilson P, Breusegem S, Barry N, Blaine J, Jiang T, Wang XX, Levi M (2009) Regulation of rat intestinal Na-dependent phosphate transporters by dietary phosphate. Am J Physiol Renal Physiol 297:F1466–F1475. https://doi.org/10.1152/ajprenal.00279.2009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Gisler SM, Kittanakom S, Fuster D, Wong V, Bertic M, Radanovic T, Hall RA, Murer H, Biber J, Markovich D, Moe OW, Stagljar I (2008) Monitoring protein-protein interactions between the mammalian integral membrane transporters and PDZ-interacting partners using a modified split-ubiquitin membrane yeast two-hybrid system. Mol Cell Proteomics 7:1362–1377. https://doi.org/10.1074/mcp.M800079-MCP200

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB (2000) Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342:1478–1483. https://doi.org/10.1056/NEJM200005183422003

    Article  PubMed  CAS  Google Scholar 

  30. Halbritter J, Baum M, Hynes AM, Rice SJ, Thwaites DT, Gucev ZS, Fisher B, Spaneas L, Porath JD, Braun DA, Wassner AJ, Nelson CP, Tasic V, Sayer JA, Hildebrandt F (2015) Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. J Am Soc Nephrol 26:543–551. https://doi.org/10.1681/ASN.2014040388

    Article  PubMed  CAS  Google Scholar 

  31. Hernando N (2018) NaPi-IIa interacting partners and their (un)known functional roles. Pflugers Arch. https://doi.org/10.1007/s00424-018-2176-2

  32. Hernando N, Myakala K, Simona F, Knopfel T, Thomas L, Murer H, Wagner CA, Biber J (2015) Intestinal depletion of NaPi-IIb/Slc34a2 in mice: renal and hormonal adaptation. J Bone Miner Res 30:1925–1937. https://doi.org/10.1002/jbmr.2523

    Article  PubMed  CAS  Google Scholar 

  33. Hernando N, Wagner CA (2018) Mechanisms and regulation of intestinal phosphate absorption. Compr Physiol 8:1065–1090. https://doi.org/10.1002/cphy.c170024

    Article  PubMed  Google Scholar 

  34. Hilfiker H, Hattenhauer O, Traebert M, Forster I, Murer H, Biber J (1998) Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine. Proc Natl Acad Sci U S A 95:14564–14569

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Homann V, Rosin-Steiner S, Stratmann T, Arnold WH, Gaengler P, Kinne RK (2005) Sodium-phosphate cotransporter in human salivary glands: molecular evidence for the involvement of NPT2b in acinar phosphate secretion and ductal phosphate reabsorption. Arch Oral Biol 50:759–768. https://doi.org/10.1016/j.archoralbio.2005.01.009

    Article  PubMed  CAS  Google Scholar 

  36. Hu MC, Shiizaki K, Kuro-o M, Moe OW (2013) Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol 75:503–533. https://doi.org/10.1146/annurev-physiol-030212-183727

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Huqun IS, Miyazawa H, Ishii K, Uchiyama B, Ishida T, Tanaka S, Tazawa R, Fukuyama S, Tanaka T, Nagai Y, Yokote A, Takahashi H, Fukushima T, Kobayashi K, Chiba H, Nagata M, Sakamoto S, Nakata K, Takebayashi Y, Shimizu Y, Kaneko K, Shimizu M, Kanazawa M, Abe S, Inoue Y, Takenoshita S, Yoshimura K, Kudo K, Tachibana T, Nukiwa T, Hagiwara K (2007) Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis. Am J Respir Crit Care Med 175:263–268. https://doi.org/10.1164/rccm.200609-1274OC

    Article  PubMed  CAS  Google Scholar 

  38. Hureaux M, Molin A, Jay N, Saliou AH, Spaggiari E, Salomon R, Benachi A, Vargas-Poussou R, Heidet L (2018) Prenatal hyperechogenic kidneys in three cases of infantile hypercalcemia associated with SLC34A1 mutations. Pediatr Nephrol 33:1723–1729. https://doi.org/10.1007/s00467-018-3998-z

    Article  PubMed  Google Scholar 

  39. Ishihara Y, Hagiwara K, Zen K, Huqun HY, Natsuhara A (2009) A case of pulmonary alveolar microlithiasis with an intragenetic deletion in SLC34A2 detected by a genome-wide SNP study. Thorax 64:365–367. https://doi.org/10.1136/thx.2008.102996

    Article  PubMed  CAS  Google Scholar 

  40. Izumi H, Kurai J, Kodani M, Watanabe M, Yamamoto A, Nanba E, Adachi K, Igishi T, Shimizu E (2017) A novel SLC34A2 mutation in a patient with pulmonary alveolar microlithiasis. Hum Genome Var 4:16047. https://doi.org/10.1038/hgv.2016.47

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Jacquillet G, Unwin RJ (2018) Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi). Pflugers Arch. https://doi.org/10.1007/s00424-018-2231-z

  42. Jonsson AL, Simonsen U, Hilberg O, Bendstrup E (2012) Pulmonary alveolar microlithiasis: two case reports and review of the literature. Eur Respir Rev 21:249–256. https://doi.org/10.1183/09059180.00009411

    Article  PubMed  Google Scholar 

  43. Karim Z, Gerard B, Bakouh N, Alili R, Leroy C, Beck L, Silve C, Planelles G, Urena-Torres P, Grandchamp B, Friedlander G, Prie D (2008) NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med 359:1128–1135. https://doi.org/10.1056/NEJMoa0802836

    Article  PubMed  CAS  Google Scholar 

  44. Katai K, Tanaka H, Tatsumi S, Fukunaga Y, Genjida K, Morita K, Kuboyama N, Suzuki T, Akiba T, Miyamoto K, Takeda E (1999) Nicotinamide inhibits sodium-dependent phosphate cotransport activity in rat small intestine. Nephrol Dial Transplant 14:1195–1201

    Article  PubMed  CAS  Google Scholar 

  45. Kato Y, Ninomiya K, Ohashi K, Tomida S, Makimoto G, Watanabe H, Kudo K, Matsumoto S, Umemura S, Goto K, Ichihara E, Ninomiya T, Kubo T, Sato A, Hotta K, Tabata M, Toyooka S, Maeda Y, Kiura K (2018) Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions. Cancer Sci 109:3149–3158. https://doi.org/10.1111/cas.13752

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Kempson SA, Colon-Otero G, Ou SY, Turner ST, Dousa TP (1981) Possible role of nicotinamide adenine dinucleotide as an intracellular regulator of renal transport of phosphate in the rat. J Clin Invest 67:1347–1360

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Kenny J, Lees MM, Drury S, Barnicoat A, Van't Hoff W, Palmer R, Morrogh D, Waters JJ, Lench NJ, Bockenhauer D (2011) Sotos syndrome, infantile hypercalcemia, and nephrocalcinosis: a contiguous gene syndrome. Pediatr Nephrol 26:1331–1334. https://doi.org/10.1007/s00467-011-1884-z

    Article  PubMed  Google Scholar 

  48. Kestenbaum B, Glazer NL, Kottgen A, Felix JF, Hwang SJ, Liu Y, Lohman K, Kritchevsky SB, Hausman DB, Petersen AK, Gieger C, Ried JS, Meitinger T, Strom TM, Wichmann HE, Campbell H, Hayward C, Rudan I, de Boer IH, Psaty BM, Rice KM, Chen YD, Li M, Arking DE, Boerwinkle E, Coresh J, Yang Q, Levy D, van Rooij FJ, Dehghan A, Rivadeneira F, Uitterlinden AG, Hofman A, van Duijn CM, Shlipak MG, Kao WH, Witteman JC, Siscovick DS, Fox CS (2010) Common genetic variants associate with serum phosphorus concentration. J Am Soc Nephrol 21:1223–1232. https://doi.org/10.1681/ASN.2009111104

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Kestenbaum B, Sampson JN, Rudser KD, Patterson DJ, Seliger SL, Young B, Sherrard DJ, Andress DL (2005) Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 16:520–528. https://doi.org/10.1681/ASN.2004070602

    Article  PubMed  CAS  Google Scholar 

  50. Khadeer MA, Tang Z, Tenenhouse HS, Eiden MV, Murer H, Hernando N, Weinman EJ, Chellaiah MA, Gupta A (2003) Na+-dependent phosphate transporters in the murine osteoclast: cellular distribution and protein interactions. Am J Physiol Cell Physiol 284:C1633–C1644. https://doi.org/10.1152/ajpcell.00580.2002

    Article  PubMed  CAS  Google Scholar 

  51. Khan SR, Glenton PA (2008) Calcium oxalate crystal deposition in kidneys of hypercalciuric mice with disrupted type IIa sodium-phosphate cotransporter. Am J Physiol Renal Physiol 294:F1109–F1115. https://doi.org/10.1152/ajprenal.00620.2007

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. King AJ, Siegel M, He Y, Nie B, Wang J, Koo-McCoy S, Minassian NA, Jafri Q, Pan D, Kohler J, Kumaraswamy P, Kozuka K, Lewis JG, Dragoli D, Rosenbaum DP, O'Neill D, Plain A, Greasley PJ, Jonsson-Rylander AC, Karlsson D, Behrendt M, Stromstedt M, Ryden-Bergsten T, Knopfel T, Pastor Arroyo EM, Hernando N, Marks J, Donowitz M, Wagner CA, Alexander RT, Caldwell JS (2018) Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability. Sci Transl Med 10:eaam6474. https://doi.org/10.1126/scitranslmed.aam6474

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Knopfel T, Pastor-Arroyo EM, Schnitzbauer U, Kratschmar DV, Odermatt A, Pellegrini G, Hernando N, Wagner CA (2017) The intestinal phosphate transporter NaPi-IIb (Slc34a2) is required to protect bone during dietary phosphate restriction. Sci Rep 7:11018. https://doi.org/10.1038/s41598-017-10390-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Köhler K, Forster IC, Lambert G, Biber J, Murer H (2000) The functional unit of the renal type IIa Na+/Pi cotransporter is a monomer. J Biol Chem 275:26113–26120

    Article  PubMed  Google Scholar 

  55. Kottgen A, Glazer NL, Dehghan A, Hwang SJ, Katz R, Li M, Yang Q, Gudnason V, Launer LJ, Harris TB, Smith AV, Arking DE, Astor BC, Boerwinkle E, Ehret GB, Ruczinski I, Scharpf RB, Chen YD, de Boer IH, Haritunians T, Lumley T, Sarnak M, Siscovick D, Benjamin EJ, Levy D, Upadhyay A, Aulchenko YS, Hofman A, Rivadeneira F, Uitterlinden AG, van Duijn CM, Chasman DI, Pare G, Ridker PM, Kao WH, Witteman JC, Coresh J, Shlipak MG, Fox CS (2009) Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 41:712–717. https://doi.org/10.1038/ng.377

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Kottgen A, Pattaro C, Boger CA, Fuchsberger C, Olden M, Glazer NL, Parsa A, Gao X, Yang Q, Smith AV, O’Connell JR, Li M, Schmidt H, Tanaka T, Isaacs A, Ketkar S, Hwang SJ, Johnson AD, Dehghan A, Teumer A, Pare G, Atkinson EJ, Zeller T, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tonjes A, Hayward C, Aspelund T, Eiriksdottir G, Launer LJ, Harris TB, Rampersaud E, Mitchell BD, Arking DE, Boerwinkle E, Struchalin M, Cavalieri M, Singleton A, Giallauria F, Metter J, de Boer IH, Haritunians T, Lumley T, Siscovick D, Psaty BM, Zillikens MC, Oostra BA, Feitosa M, Province M, de Andrade M, Turner ST, Schillert A, Ziegler A, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Illig T, Klopp N, Meisinger C, Wichmann HE, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Schreiber S, Aulchenko YS, Felix JF, Rivadeneira F, Uitterlinden AG, Hofman A, Imboden M, Nitsch D, Brandstatter A, Kollerits B, Kedenko L, Magi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Volzke H, Kroemer HK, Nauck M, Volker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Blankenberg S, Liu Y, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Gudnason V, Shuldiner AR, Coresh J, Schmidt R, Ferrucci L, Shlipak MG, van Duijn CM, Borecki I, Kramer BK, Rudan I, Gyllensten U, Wilson JF, Witteman JC, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS (2010) New loci associated with kidney function and chronic kidney disease. Nat Genet 42:376–384. https://doi.org/10.1038/ng.568

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Kurnaz E, Savas Erdeve S, Cetinkaya S, Aycan Z (2018) Rare cause of infantile hypercalcemia: a novel mutation in the SLC34A1 gene. Horm Res Paediatr 18:1–7. https://doi.org/10.1159/000492899

  58. Labonte ED, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, He L, Dy E, Black D, Zhong Z, Langsetmo I, Spencer AG, Bell N, Deshpande D, Navre M, Lewis JG, Jacobs JW, Charmot D (2015) Gastrointestinal inhibition of sodium-hydrogen exchanger 3 reduces phosphorus absorption and protects against vascular calcification in CKD. J Am Soc Nephrol 26:1138–1149. https://doi.org/10.1681/ASN.2014030317

    Article  PubMed  CAS  Google Scholar 

  59. Lacerda-Abreu MA, Russo-Abrahao T, Monteiro RQ, Rumjanek FD, Meyer-Fernandes JR (2018) Inorganic phosphate transporters in cancer: functions, molecular mechanisms and possible clinical applications. Biochim Biophys Acta Rev Cancer 1870:291–298. https://doi.org/10.1016/j.bbcan.2018.05.001

    Article  PubMed  CAS  Google Scholar 

  60. Lapointe J-Y, Tessier J, Paquette Y, Wallendorff B, Coady M, Pichette V, Bonnardeaux A (2006) NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak. Kidney Int 69:2261–2267

    Article  PubMed  CAS  Google Scholar 

  61. Larsson TE, Kameoka C, Nakajo I, Taniuchi Y, Yoshida S, Akizawa T, Smulders RA (2018) NPT-IIb inhibition does not improve hyperphosphatemia in CKD. Kidney Int Rep 3:73–80. https://doi.org/10.1016/j.ekir.2017.08.003

    Article  PubMed  Google Scholar 

  62. Ledo N, Ko YA, Park AS, Kang HM, Han SY, Choi P, Susztak K (2015) Functional genomic annotation of genetic risk loci highlights inflammation and epithelial biology networks in CKD. J Am Soc Nephrol 26:692–714. https://doi.org/10.1681/ASN.2014010028

    Article  PubMed  CAS  Google Scholar 

  63. Lindegren S, Andrade LN, Back T, Machado CM, Horta BB, Buchpiguel C, Moro AM, Okamoto OK, Jacobsson L, Cederkrantz E, Washiyama K, Aneheim E, Palm S, Jensen H, Tuma MC, Chammas R, Hultborn R, Albertsson P (2015) Binding affinity, specificity and comparative biodistribution of the parental murine monoclonal antibody MX35 (anti-NaPi2b) and its humanized version Rebmab200. PLoS One 10:e0126298. https://doi.org/10.1371/journal.pone.0126298

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Lundquist P, Ritchie HH, Moore K, Lundgren T, Linde A (2002) Phosphate and calcium uptake by rat odontoblast-like MRPC-1 cells concomitant with mineralization. J Bone Miner Res 17:1801–1813. https://doi.org/10.1359/jbmr.2002.17.10.1801

    Article  PubMed  CAS  Google Scholar 

  65. Ma T, Qu D, Yan B, Zhang Q, Ren J, Hu Y (2018) Effect of SLC34A2 gene mutation on extracellular phosphorus transport in PAM alveolar epithelial cells. Exp Ther Med 15:310–314. https://doi.org/10.3892/etm.2017.5380

    Article  PubMed  CAS  Google Scholar 

  66. Ma T, Ren J, Yin J, Ma Z (2014) A pedigree with pulmonary alveolar microlithiasis: a clinical case report and literature review. Cell Biochem Biophys 70:565–572. https://doi.org/10.1007/s12013-014-9957-9

    Article  PubMed  CAS  Google Scholar 

  67. Magen D, Berger L, Coady MJ, Ilivitzki A, Militianu D, Tieder M, Selig S, Lapointe JY, Zelikovic I, Skorecki K (2010) A loss-of-function mutation in NaPi-IIa and renal Fanconi’s syndrome. N Engl J Med 362:1102–1109. https://doi.org/10.1056/NEJMoa0905647

    Article  PubMed  CAS  Google Scholar 

  68. Mahajan A, Rodan AR, Le TH, Gaulton KJ, Haessler J, Stilp AM, Kamatani Y, Zhu G, Sofer T, Puri S, Schellinger JN, Chu PL, Cechova S, van Zuydam N, Arnlov J, Flessner MF, Giedraitis V, Heath AC, Kubo M, Larsson A, Lindgren CM, Madden PA, Montgomery GW, Papanicolaou GJ, Reiner AP, Sundstrom J, Thornton TA, Lind L, Ingelsson E, Cai J, Martin NG, Kooperberg C, Matsuda K, Whitfield JB, Okada Y, Laurie CC, Morris AP, Franceschini N (2016) Trans-ethnic fine mapping highlights kidney-function genes linked to salt sensitivity. Am J Hum Genet 99:636–646. https://doi.org/10.1016/j.ajhg.2016.07.012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Marks J, Srai SK, Biber J, Murer H, Unwin RJ, Debnam ES (2006) Intestinal phosphate absorption and the effect of vitamin D: a comparison of rats with mice. Exp Physiol 91:531–537. https://doi.org/10.1113/expphysiol.2005.032516

    Article  PubMed  CAS  Google Scholar 

  70. Marx SJ, Lourenco DM Jr (2017) Familial hyperparathyroidism - disorders of growth and secretion in hormone-secretory tissue. Horm Metab Res 49:805–815. https://doi.org/10.1055/s-0043-120670

    Article  PubMed  CAS  Google Scholar 

  71. Miyagawa A, Tatsumi S, Takahama W, Fujii O, Nagamoto K, Kinoshita E, Nomura K, Ikuta K, Fujii T, Hanazaki A, Kaneko I, Segawa H, Miyamoto KI (2018) The sodium phosphate cotransporter family and nicotinamide phosphoribosyltransferase contribute to the daily oscillation of plasma inorganic phosphate concentration. Kidney Int 93:1073–1085. https://doi.org/10.1016/j.kint.2017.11.022

    Article  PubMed  CAS  Google Scholar 

  72. Monico CG, Milliner DS (2012) Genetic determinants of urolithiasis. Nat Rev Nephrol 8:151–162. https://doi.org/10.1038/nrneph.2011.211

    Article  CAS  Google Scholar 

  73. Muscher-Banse AS, Breves G (2018) Mechanisms and regulation of epithelial phosphate transport in ruminants: approaches in comparative physiology. Pflugers Arch. https://doi.org/10.1007/s00424-018-2181-5

  74. Oddsson A, Sulem P, Helgason H, Edvardsson VO, Thorleifsson G, Sveinbjornsson G, Haraldsdottir E, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Masson G, Holm H, Gudbjartsson DF, Thorsteinsdottir U, Indridason OS, Palsson R, Stefansson K (2015) Common and rare variants associated with kidney stones and biochemical traits. Nat Commun 6:7975. https://doi.org/10.1038/ncomms8975

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Ozbudak IH, Bassorgun CI, Ozbilim G, Luleci G, Sarper A, Erdogan A, Taylan F, Altiok E (2012) Pulmonary alveolar microlithiasis with homozygous c.316G > C (p.G106R) mutation: a case report. Turk Patoloji Derg 28:282–285. https://doi.org/10.5146/tjpath.2012.01138

    Article  PubMed  Google Scholar 

  76. Pattaro C, Teumer A, Gorski M, Chu AY, Li M, Mijatovic V, Garnaas M, Tin A, Sorice R, Li Y, Taliun D, Olden M, Foster M, Yang Q, Chen MH, Pers TH, Johnson AD, Ko YA, Fuchsberger C, Tayo B, Nalls M, Feitosa MF, Isaacs A, Dehghan A, d'Adamo P, Adeyemo A, Dieffenbach AK, Zonderman AB, Nolte IM, van der Most PJ, Wright AF, Shuldiner AR, Morrison AC, Hofman A, Smith AV, Dreisbach AW, Franke A, Uitterlinden AG, Metspalu A, Tonjes A, Lupo A, Robino A, Johansson A, Demirkan A, Kollerits B, Freedman BI, Ponte B, Oostra BA, Paulweber B, Kramer BK, Mitchell BD, Buckley BM, Peralta CA, Hayward C, Helmer C, Rotimi CN, Shaffer CM, Muller C, Sala C, van Duijn CM, Saint-Pierre A, Ackermann D, Shriner D, Ruggiero D, Toniolo D, Lu Y, Cusi D, Czamara D, Ellinghaus D, Siscovick DS, Ruderfer D, Gieger C, Grallert H, Rochtchina E, Atkinson EJ, Holliday EG, Boerwinkle E, Salvi E, Bottinger EP, Murgia F, Rivadeneira F, Ernst F, Kronenberg F, Hu FB, Navis GJ, Curhan GC, Ehret GB, Homuth G, Coassin S, Thun GA, Pistis G, Gambaro G, Malerba G, Montgomery GW, Eiriksdottir G, Jacobs G, Li G, Wichmann HE, Campbell H, Schmidt H, Wallaschofski H, Volzke H, Brenner H, Kroemer HK, Kramer H, Lin H, Leach IM, Ford I, Guessous I, Rudan I, Prokopenko I, Borecki I, Heid IM, Kolcic I, Persico I, Jukema JW, Wilson JF, Felix JF, Divers J, Lambert JC, Stafford JM, Gaspoz JM, Smith JA, Faul JD, Wang JJ, Ding J, Hirschhorn JN, Attia J, Whitfield JB, Chalmers J, Viikari J, Coresh J, Denny JC, Karjalainen J, Fernandes JK, Endlich K, Butterbach K, Keene KL, Lohman K, Portas L, Launer LJ, Lyytikainen LP, Yengo L, Franke L, Ferrucci L, Rose LM, Kedenko L, Rao M, Struchalin M, Kleber ME, Cavalieri M, Haun M, Cornelis MC, Ciullo M, Pirastu M, de Andrade M, McEvoy MA, Woodward M, Adam M, Cocca M, Nauck M, Imboden M, Waldenberger M, Pruijm M, Metzger M, Stumvoll M, Evans MK, Sale MM, Kahonen M, Boban M, Bochud M, Rheinberger M, Verweij N, Bouatia-Naji N, Martin NG, Hastie N, Probst-Hensch N, Soranzo N, Devuyst O, Raitakari O, Gottesman O, Franco OH, Polasek O, Gasparini P, Munroe PB, Ridker PM, Mitchell P, Muntner P, Meisinger C, Smit JH, Kovacs P, Wild PS, Froguel P, Rettig R, Magi R, Biffar R, Schmidt R, Middelberg RP, Carroll RJ, Penninx BW, Scott RJ, Katz R, Sedaghat S, Wild SH, Kardia SL, Ulivi S, Hwang SJ, Enroth S, Kloiber S, Trompet S, Stengel B, Hancock SJ, Turner ST, Rosas SE, Stracke S, Harris TB, Zeller T, Zemunik T, Lehtimaki T, Illig T, Aspelund T, Nikopensius T, Esko T, Tanaka T, Gyllensten U, Volker U, Emilsson V, Vitart V, Aalto V, Gudnason V, Chouraki V, Chen WM, Igl W, Marz W, Koenig W, Lieb W, Loos RJ, Liu Y, Snieder H, Pramstaller PP, Parsa A, O'Connell JR, Susztak K, Hamet P, Tremblay J, de Boer IH, Boger CA, Goessling W, Chasman DI, Kottgen A, Kao WH, Fox CS (2016) Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. Nat Commun 7:10023. https://doi.org/10.1038/ncomms10023

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Pavik I, Jaeger P, Ebner L, Wagner CA, Petzold K, Spichtig D, Poster D, Wuthrich RP, Russmann S, Serra AL (2013) Secreted klotho and FGF23 in chronic kidney disease stage 1 to 5: a sequence suggested from a cross-sectional study. Nephrol Dial Transplant 28:352–359. https://doi.org/10.1093/ndt/gfs460

    Article  PubMed  CAS  Google Scholar 

  78. Prie D, Huart V, Bakouh N, Planelles G, Dellis O, Gerard B, Hulin P, Benque-Blanchet F, Silve C, Grandchamp B, Friedlander G (2002) Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N Engl J Med 347:983–991

    Article  PubMed  CAS  Google Scholar 

  79. Pronicka E, Ciara E, Halat P, Janiec A, Wojcik M, Rowinska E, Rokicki D, Pludowski P, Wojciechowska E, Wierzbicka A, Ksiazyk JB, Jacoszek A, Konrad M, Schlingmann KP, Litwin M (2017) Biallelic mutations in CYP24A1 or SLC34A1 as a cause of infantile idiopathic hypercalcemia (IIH) with vitamin D hypersensitivity: molecular study of 11 historical IIH cases. J Appl Genet 58:349–353. https://doi.org/10.1007/s13353-017-0397-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Radanovic T, Wagner CA, Murer H, Biber J (2005) Regulation of intestinal phosphate transport. I. Segmental expression and adaptation to low-P(i) diet of the type IIb Na(+)-P(i) cotransporter in mouse small intestine. Am J Physiol Gastrointest Liver Physiol 288:G496–G500. https://doi.org/10.1152/ajpgi.00167.2004

    Article  PubMed  CAS  Google Scholar 

  81. Rajagopal A, Debora B, James TL, Soledad K, Florencia C, Hamilton C, David L, Jose Miguel L, Graciela V, Ignacio B, Richard G, Campeau P, Lee B (2014) Exome sequencing identifies a novel homozygous mutation in the phosphate transporter SLC34A1 in hypophosphatemia and nephrocalcinosis. J Clin Endocrinol Metab:jc20141517. https://doi.org/10.1210/jc.2014-1517

  82. Ritter CS, Slatopolsky E (2016) Phosphate toxicity in CKD: the killer among us. Clin J Am Soc Nephrol 11:1088–1100. https://doi.org/10.2215/CJN.11901115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Robinson-Cohen C, Bartz TM, Lai D, Ikizler TA, Peacock M, Imel EA, Michos ED, Foroud TM, Akesson K, Taylor KD, Malmgren L, Matsushita K, Nethander M, Eriksson J, Ohlsson C, Mellstrom D, Wolf M, Ljunggren O, McGuigan F, Rotter JI, Karlsson M, Econs MJ, Ix JH, Lutsey PL, Psaty BM, de Boer IH, Kestenbaum BR (2018) Genetic variants associated with circulating fibroblast growth factor 23. J Am Soc Nephrol 29:2583–2592. https://doi.org/10.1681/ASN.2018020192

    Article  PubMed  CAS  Google Scholar 

  84. Robinson-Cohen C, Lutsey PL, Kleber ME, Nielson CM, Mitchell BD, Bis JC, Eny KM, Portas L, Eriksson J, Lorentzon M, Koller DL, Milaneschi Y, Teumer A, Pilz S, Nethander M, Selvin E, Tang W, Weng LC, Wong HS, Lai D, Peacock M, Hannemann A, Volker U, Homuth G, Nauk M, Murgia F, Pattee JW, Orwoll E, Zmuda JM, Riancho JA, Wolf M, Williams F, Penninx B, Econs MJ, Ryan KA, Ohlsson C, Paterson AD, Psaty BM, Siscovick DS, Rotter JI, Pirastu M, Streeten E, Marz W, Fox C, Coresh J, Wallaschofski H, Pankow JS, de Boer IH, Kestenbaum B (2017) Genetic variants associated with circulating parathyroid hormone. J Am Soc Nephrol 28:1553–1565. https://doi.org/10.1681/ASN.2016010069

    Article  PubMed  CAS  Google Scholar 

  85. Sabbagh Y, O'Brien SP, Song W, Boulanger JH, Stockmann A, Arbeeny C, Schiavi SC (2009) Intestinal npt2b plays a major role in phosphate absorption and homeostasis. J Am Soc Nephrol 20:2348–2358. https://doi.org/10.1681/ASN.2009050559

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Saito A, Nikolaidis NM, Amlal H, Uehara Y, Gardner JC, LaSance K, Pitstick LB, Bridges JP, Wikenheiser-Brokamp KA, McGraw DW, Woods JC, Sabbagh Y, Schiavi SC, Altinisik G, Jakopovic M, Inoue Y, McCormack FX (2015) Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment. Sci Transl Med 7:313ra181. https://doi.org/10.1126/scitranslmed.aac8577

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Schiavi SC, Tang W, Bracken C, O’Brien SP, Song W, Boulanger J, Ryan S, Phillips L, Liu S, Arbeeny C, Ledbetter S, Sabbagh Y (2012) Npt2b deletion attenuates hyperphosphatemia associated with CKD. J Am Soc Nephrol 23:1691–1700. https://doi.org/10.1681/ASN.2011121213

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Schlingmann KP, Ruminska J, Kaufmann M, Dursun I, Patti M, Kranz B, Pronicka E, Ciara E, Akcay T, Bulus D, Cornelissen EA, Gawlik A, Sikora P, Patzer L, Galiano M, Boyadzhiev V, Dumic M, Vivante A, Kleta R, Dekel B, Levtchenko E, Bindels RJ, Rust S, Forster IC, Hernando N, Jones G, Wagner CA, Konrad M (2016) Autosomal-recessive mutations in SLC34A1 encoding sodium-phosphate cotransporter 2A cause idiopathic infantile hypercalcemia. J Am Soc Nephrol 27:604–614. https://doi.org/10.1681/ASN.2014101025

    Article  PubMed  CAS  Google Scholar 

  89. Stokman L, Nossent EJ, Grunberg K, Meijboom L, Yakicier MC, Voorhoeve E, Houweling AC (2016) A case of pulmonary alveolar microlithiasis associated with a homozygous 195 kb deletion encompassing the entire SLC34A2 gene. Clin Case Rep 4:412–415. https://doi.org/10.1002/ccr3.532

    Article  PubMed  PubMed Central  Google Scholar 

  90. Tafaj O, Juppner H (2017) Pseudohypoparathyroidism: one gene, several syndromes. J Endocrinol Investig 40:347–356. https://doi.org/10.1007/s40618-016-0588-4

    Article  CAS  Google Scholar 

  91. Takahashi Y, Tanaka A, Nakamura T, Fukuwatari T, Shibata K, Shimada N, Ebihara I, Koide H (2004) Nicotinamide suppresses hyperphosphatemia in hemodialysis patients. Kidney Int 65:1099–1104. https://doi.org/10.1111/j.1523-1755.2004.00482.x

    Article  PubMed  CAS  Google Scholar 

  92. Tatsumi S, Katai K, Kaneko I, Segawa H, Miyamoto KI (2018) NAD metabolism and the SLC34 family: evidence for a liver-kidney axis regulating inorganic phosphate. Pflugers Arch. https://doi.org/10.1007/s00424-018-2204-2

  93. Traebert M, Hattenhauer O, Murer H, Kaissling B, Biber J (1999) Expression of type II Na-P(i) cotransporter in alveolar type II cells. Am J Phys 277:L868–L873

    CAS  Google Scholar 

  94. Uno JK, Kolek OI, Hines ER, Xu H, Timmermann BN, Kiela PR, Ghishan FK (2006) The role of tumor necrosis factor alpha in down-regulation of osteoblast Phex gene expression in experimental murine colitis. Gastroenterology 131:497–509. https://doi.org/10.1053/j.gastro.2006.05.020

    Article  PubMed  CAS  Google Scholar 

  95. Urabe Y, Tanikawa C, Takahashi A, Okada Y, Morizono T, Tsunoda T, Kamatani N, Kohri K, Chayama K, Kubo M, Nakamura Y, Matsuda K (2012) A genome-wide association study of nephrolithiasis in the Japanese population identifies novel susceptible loci at 5q35.3, 7p14.3, and 13q14.1. PLoS Genet 8:e1002541. https://doi.org/10.1371/journal.pgen.1002541

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Villa-Bellosta R, Ravera S, Sorribas V, Stange G, Levi M, Murer H, Biber J, Forster IC (2009) The Na+-Pi cotransporter PiT-2 (SLC20A2) is expressed in the apical membrane of rat renal proximal tubules and regulated by dietary Pi. Am J Physiol Renal Physiol 296:F691–F699. https://doi.org/10.1152/ajprenal.90623.2008

    Article  PubMed  CAS  Google Scholar 

  97. Virkki LV, Forster IC, Hernando N, Biber J, Murer H (2003) Functional characterization of two naturally occurring mutations in the human sodium-phosphate cotransporter type IIa. J Bone Miner Res 18:2135–2141

    Article  PubMed  CAS  Google Scholar 

  98. Vismara MF, Colao E, Fabiani F, Bombardiere F, Tamburrini O, Alessio C, Manti F, Pelaia G, Romeo P, Iuliano R, Perrotti N (2015) The sodium-phosphate co-transporter SLC34A2, and pulmonary alveolar microlithiasis: presentation of an inbred family and a novel truncating mutation in exon 3. Respir Med Case Rep 16:77–80. https://doi.org/10.1016/j.rmcr.2015.08.002

    Article  PubMed  PubMed Central  Google Scholar 

  99. Wagner CA, Rubio-Aliaga I, Biber J, Hernando N (2014) Genetic diseases of renal phosphate handling. Nephrol Dial Transplant 29(Suppl 4):iv45–iv54. https://doi.org/10.1093/ndt/gfu217

    Article  PubMed  CAS  Google Scholar 

  100. Wagner CA, Rubio-Aliaga I, Hernando N (2017) Renal phosphate handling and inherited disorders of phosphate reabsorption: an update. Pediatr Nephrol. https://doi.org/10.1007/s00467-017-3873-3

  101. Wang B, Yang Y, Liu L, Blair HC, Friedman PA (2013) NHERF1 regulation of PTH-dependent bimodal Pi transport in osteoblasts. Bone 52:268–277. https://doi.org/10.1016/j.bone.2012.10.001

    Article  PubMed  CAS  Google Scholar 

  102. Wang H, Yin X, Wu D, Jiang X (2014) SLC34A2 gene compound heterozygous mutation identification in a patient with pulmonary alveolar microlithiasis and computational 3D protein structure prediction. Meta Gene 2:557–564. https://doi.org/10.1016/j.mgene.2014.07.004

    Article  PubMed  PubMed Central  Google Scholar 

  103. Xu H, Inouye M, Hines ER, Collins JF, Ghishan FK (2003) Transcriptional regulation of the human NaPi-IIb cotransporter by EGF in Caco-2 cells involves c-myb. Am J Physiol Cell Physiol 284:C1262–C1271. https://doi.org/10.1152/ajpcell.00456.2002

    Article  PubMed  CAS  Google Scholar 

  104. Xu H, Uno JK, Inouye M, Xu L, Drees JB, Collins JF, Ghishan FK (2003) Regulation of intestinal NaPi-IIb cotransporter gene expression by estrogen. Am J Physiol Gastrointest Liver Physiol 285:G1317–G1324

    Article  PubMed  CAS  Google Scholar 

  105. Yasui T, Okada A, Urabe Y, Usami M, Mizuno K, Kubota Y, Tozawa K, Sasaki S, Higashi Y, Sato Y, Kubo M, Nakamura Y, Matsuda K, Kohri K (2013) A replication study for three nephrolithiasis loci at 5q35.3, 7p14.3 and 13q14.1 in the Japanese population. J Hum Genet 58:588–593. https://doi.org/10.1038/jhg.2013.59

    Article  PubMed  CAS  Google Scholar 

  106. Yin X, Wang H, Wu D, Zhao G, Shao J, Dai Y (2013) SLC34A2 gene mutation of pulmonary alveolar microlithiasis: report of four cases and review of literatures. Respir Med 107:217–222. https://doi.org/10.1016/j.rmed.2012.10.016

    Article  PubMed  Google Scholar 

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Acknowledgements

Research in the laboratories of the authors has been supported by the Department of Veterans Affairs and the University of Louisville School of Medicine to E. Lederer and by the Swiss National Science Foundation (SNSF) (NCCR Kidney.CH and 31003A_176125).

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This article is part of the special issue on Phosphate transport in Pflügers Archiv – European Journal of Physiology

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Lederer, E., Wagner, C.A. Clinical aspects of the phosphate transporters NaPi-IIa and NaPi-IIb: mutations and disease associations. Pflugers Arch - Eur J Physiol 471, 137–148 (2019). https://doi.org/10.1007/s00424-018-2246-5

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