Novel NaPi-2c mutations that cause mistargeting of NaPi-2c protein and uncoupling of Na-P i cotransport cause HHRH
2008; American Physical Society; Volume: 295; Issue: 2 Linguagem: Inglês
10.1152/ajprenal.90327.2008
ISSN1931-857X
Autores Tópico(s)Medical Imaging and Pathology Studies
ResumoEDITORIAL FOCUSNovel NaPi-2c mutations that cause mistargeting of NaPi-2c protein and uncoupling of Na-Pi cotransport cause HHRHMoshe LeviMoshe LeviPublished Online:01 Aug 2008https://doi.org/10.1152/ajprenal.90327.2008This is the final version - click for previous versionMoreSectionsPDF (41 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive inherited disorder of mineral and bone metabolism. It is characterized by hypophosphatemia, rickets, and increased serum 1,25-dihydroxyvitamin D concentration, resulting in secondary absortive hypercalciuria and is also associated with renal calcification and renal stone disease (4, 8, 10, 11, 12, 14). HHRH is different than X-linked hypophosphatemia (XLH) and tumor-induced hypophosphatemia because of the increased serum 1,25-dihydroxyvitamin D levels and normal or low parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) levels (1, 5).In 2006 three publications reported mutations in the gene encoding the renal proximal tubular sodium-phosphate cotransporter NaPi-2c (SLC34A3) as the genetic cause of HHRH (3, 5, 9). However, the molecular mechanisms explaining how these mutations resulted in impaired renal tubular NaPi transport remained largely unknown until the study by Jaureguiberry et al. (6).NaPi-2c along with NaPi-2a (SLC34A1) belong to the type II class of renal proximal tubular sodium-phosphate cotransporters. However, the expression profile of NaPi-2c (S1 segment) is quite different than NaPi-2a (S1–S3 segments of the renal proximal tubule). In addition, the regulation of NaPi-2c by dietary phosphate (Pi) and PTH follows a different pattern and time course than NaPi-2a. There may well be species differences in the expression level and regulation of NaPi-2a and NaPi-2c; however, it is clear that both transporters are necessary for normal and full Pi reabsorptive capacity of the renal proximal tubule (2, 7).The study by Jaureguiberry et al. (6) describes two novel compound heterozygous mutations, c.410C > T (p.T137M) (T137M) on the maternal and g.4225_50del on the paternal allele of SLC34A3, in a previously reported male with HHRH and recurrent kidney stones. For functional analysis in vitro, the investigators generated expression plasmids encoding enhanced green fluorescence protein (EGFP) tagged to the NH2 terminus of wild-type or mutant human NaPi-IIc: 1) EGFP-hNaPi-IIc; 2) EGFP-(M137)hNaPi-IIc, representing the maternal mutation; and 3) EGFP-(Stop446)hNaPi-IIc, representing the paternal mutation (the V466Stop mutation truncates NaPi-IIc after amino acid 446, which represents one possible reading frame for g.4225_50del).The V446Stop mutant showed complete loss of expression and function when assayed for apical membrane expression in opossum kidney (OK) cells and sodium-dependent phosphate uptake into Xenopus laevis oocytes. The cause of the impaired apical membrane expression is not known but may include dysfunctional interactions with sodium-hydrogen exchanger regulator 1 and/or sodium-hydrogen exchanger regulator 3, which recently were shown to be important for NaPi-2c apical membrane expression (13), and perhaps other apical membrane-targeting proteins.In comparison, the apical membrane expression of the T137M mutant EGFP-(M137)hNaPi-IIc in OK cells was reduced by 60%, and after correction for surface expression, the rate of sodium-dependent phosphate uptake by oocytes was decreased by an additional 60%.The resulting overall highly significant reduction in function of the T137M NaPi-IIc mutation together with complete loss of expression and function of the g.4225_50del (V446Stop) mutation thus appear to be sufficient to explain the hypophosphatemic phenotype in the patient.Interestingly, additional dual isotope sodium-phosphate uptake experiments in oocytes indicated that the stoichiometric ratio of 22Na and 33P uptake was increased to 7.1 ± 3.65 for EGFP-(M137)hNaPi-IIc compared with wild-type. Two-electrode studies indicated that EGFP-(M137)hNaPi-IIc is nonelectrogenic, but displayed a significant phosphate-independent inward-rectified sodium current, which appeared to be insensitive to phosphonoformic acid, an inhibitor of sodium gradient-dependent phosphate transport.M137 may therefore impair sodium-phosphate cotransport by increasing sodium uptake which may 1) decrease the sodium gradient that is needed for sodium gradient-dependent phosphate uptake, 2) increase internalization of NaPi-2c cotransporters from the apical membrane, or 3) decrease exocytosis of the NaPi-2c cotransporters to the apical membrane. In addition, it is also possible that these mutations may be associated with alterations in the posttranslational modification of the NaPi-2c protein, including glycosylation, phosphorylation, and ubiquitinylation.Furthermore, this mutation may also alter the function of other proximal tubular apical membrane cotransporters such as the sodium-hydrogen exchanger (NHE3), the sodium-sulfate cotransporter (Na-Si), and the sodium-citrate cotransporter (Na-citrate), which could also impair urinary acidification and citrate excretion, and therefore play an important role in urinary stone formation.The study by Jaureguiberry et al. (6) therefore provides novel insights into how mutations in NaPi-2c may result in hypophosphatemia in HHRH. The rare but highly novel and important HHRH mutations may teach us about the importance of NaPi-2c in the regulation of human renal phosphate transport and also possibly novel causative factors for renal stone formation and renal calcification.REFERENCES1 Bastepe M, Juppner H. Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation. Rev Endocr Metab Disord 9: 171–180, 2008.Crossref | PubMed | ISI | Google Scholar2 Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci USA 95: 5372–5377, 1998.Crossref | PubMed | ISI | Google Scholar3 Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, Frappier D, Burkett K, Carpenter TO, Anderson D, Garabedian M, Sermet I, Fujiwara TM, Morgan K, Tenenhouse HS, Juppner H. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Am J Hum Genet 78: 179–192, 2006.Crossref | PubMed | ISI | Google Scholar4 Gazit D, Tieder M, Liberman UA, Passi-Even L, Bab IA. Osteomalacia in hereditary hypophosphatemic rickets with hypercalciuria: a correlative clinical-histomorphometric study. J Clin Endocrinol Metab 72: 229–235, 1991.Crossref | PubMed | ISI | Google Scholar5 Ichikawa S, Sorenson AH, Imel EA, Friedman NE, Gertner JM, Econs MJ. Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria. J Clin Endocrinol Metab 91: 4022–4027, 2006.Crossref | PubMed | ISI | Google Scholar6 Jaureguiberry G, Carpenter TO, Forman S, Jüppner H, Bergwitz C. A novel missense mutation in SLC34A3 that causes hereditary hypophosphatemic rickets with hypercalciuria in humans identifies threonine 137 as an important determinant of sodium-phosphate cotransport in NaPi-IIc. Am J Physiol Renal Physiol (First published May 14, 2008). doi:10.1152/ajprenal.00090.2008.Link | ISI | Google Scholar7 Jones A, Tzenova J, Frappier D, Crumley M, Roslin N, Kos C, Tieder M, Langman C, Proesmans W, Carpenter T, Rice A, Anderson D, Morgan K, Fujiwara T, Tenenhouse H. Hereditary hypophosphatemic rickets with hypercalciuria is not caused by mutations in the Na/Pi cotransporter NPT2 gene. J Am Soc Nephrol 12: 507–514, 2001.PubMed | ISI | Google Scholar8 Kagitani K, Yamamoto T, Miki K, Matsumoto S, Shima M, Tajiri H, Harada T, Okada S. Hypophosphatemic rickets accompanying congenital microvillous atrophy. J Bone Miner Res 13: 1946–1952, 1998.Crossref | PubMed | ISI | Google Scholar9 Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, Gershoni-Baruch R, Albers N, Lichtner P, Schnabel D, Hochberg Z, Strom TM. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am J Hum Genet 78: 193–201, 2006.Crossref | PubMed | ISI | Google Scholar10 Tieder M, Arie R, Bab I, Maor J, Liberman UA. A new kindred with hereditary hypophosphatemic rickets with hypercalciuria: implications for correct diagnosis and treatment. Nephron 62: 176–181, 1992.Crossref | PubMed | ISI | Google Scholar11 Tieder M, Modai D, Shaked U, Samuel R, Arie R, Halabe A, Maor J, Weissgarten J, Averbukh Z, Cohen N, Edelstein S, Lieberman UA. “Idiopathic” hypercalciuria and hereditary hypophosphatemic rickets. Two phenotypical expressions of a common genetic defect. N Engl J Med 316: 125–129, 1987.Crossref | PubMed | ISI | Google Scholar12 Vargas-Poussou R, Cochat P, Le Pottier N, Roncelin I, Liutkus A, Blanchard A, Jeunemaitre X. Report of a family with two different hereditary diseases leading to early nephrocalcinosis. Pediatr Nephrol 23: 149–153, 2008.Crossref | PubMed | ISI | Google Scholar13 Villa-Bellosta R, Barac-Nieto M, Breusegem SY, Barry NP, Levi M, Sorribas V. Interactions of the growth-related, type IIc renal sodium/phosphate cotransporter with PDZ proteins. Kidney Int 73: 456–464, 2008.Crossref | PubMed | ISI | Google Scholar14 Yamamoto T, Michigami T, Aranami F, Segawa H, Yoh K, Nakajima S, Miyamoto K, Ozono K. Hereditary hypophosphatemic rickets with hypercalciuria: a study for the phosphate transporter gene type IIc and osteoblastic function. J Bone Miner Metab 25: 407–413, 2007.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: M. Levi, Div. of Renal Diseases and Hyperstension, Univ. of Colorado Denver, 4200 East 9th Ave., BRB 451, Denver, CO 80262 (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByGenetic Disorders of Phosphate HomeostasisFGF23 as a Novel Therapeutic TargetA Nonaggregating Surfactant Protein C Mutant Is Misdirected to Early Endosomes and Disrupts Phospholipid Recycling28 June 2011 | Traffic, Vol. 12, No. 9Recent advances in renal phosphate handling23 February 2010 | Nature Reviews Nephrology, Vol. 6, No. 4Genetic Disorders of Phosphate HomeostasisDifferential regulation of the renal sodium-phosphate cotransporters NaPi-IIa, NaPi-IIc, and PiT-2 in dietary potassium deficiencySophia Y. Breusegem, Hideaki Takahashi, Hector Giral-Arnal, Xiaoxin Wang, Tao Jiang, Jill W. Verlander, Paul Wilson, Shinobu Miyazaki-Anzai, Eileen Sutherland, Yupanqui Caldas, Judith T. Blaine, Hiroko Segawa, Ken-ichi Miyamoto, Nicholas P. Barry, and Moshe Levi1 August 2009 | American Journal of Physiology-Renal Physiology, Vol. 297, No. 2 More from this issue > Volume 295Issue 2August 2008Pages F369-F370 Copyright & PermissionsCopyright © 2008 the American Physiological Societyhttps://doi.org/10.1152/ajprenal.90327.2008PubMed18524854History Published online 1 August 2008 Published in print 1 August 2008 Metrics
Referência(s)