Molecular Genetics of Inherited Hypophosphataemias

Abstract

Hypophosphataemia due to isolated renal phosphate wasting comprises a genetically heterogeneous group of diseases, generally associated with rickets and osteomalacia. These inherited disorders comprise X‐linked hypophosphataemic rickets (XLH), autosomal dominant hypophosphataemic rickets (ADHR), autosomal recessive hypophosphataemic rickets (ARHR) and hereditary hypophosphataemic rickets with hypercalciuria (HHRH). XLH is the most common disorder. The gene mutated is PHEX (from Phosphate‐regulating gene with homologies to endopeptidades on X‐chromosome) which encodes an ectoenzyme of the endopeptidase family. The phosphaturic factor FGF23 (fibroblast growth factor) was found increased in XLHs and is also increased in its closely related animal model, the HYP mouse. ADHR clinically resembles XLH. The disease results from accumulation of mutated FGF23 because of impaired proteolytic degradation. ARHR results from homozygous mutations in DMP1 (dentin matrix protein 1) gene, which encodes a noncollagenous bone matrix protein DMP1.In this disease, FGF23 is elevated, suggesting that DMP1 may regulate FGF23 expression. Finally, HHRH results in mutations in SLC34A3, the gene encoding the renal sodium‐phosphate cotransporter NaPi‐IIc.

Key concepts

  • Hypophosphataemia due to isolated renal phosphate wasting is a genetically heterogeneous group of diseases. They differ from one another not only in their mode of inheritance but also in their clinical features, metabolism of vitamin D and response to therapy.

  • At least five inherited disorders have been described including X‐linked hypophosphataemic rickets (XLH), autosomal dominant hypophosphataemic rickets (ADHR) or a related disorder known as hypohosphataemic bone disease (HBD), autosomal recessive hypophosphataemic rickets (ARHR) and hereditary hypophosphataemic rickets with hypercalciuria (HHRH).

  • XLH is the most common of the inherited renal phosphate wasting disorders. The gene mutated ion this disease is PHEX (from Phosphate regulating gene with homologies to endopeptidades on X‐chromosome).

  • PHEX gene encodes a protein that closely resembles other members of the endopeptidase family. It is likely that PHEX functions either to activate or degrade a peptide hormone or related factor.

  • ADHR it produced by mutations in the phosphatonin FGF23 (fibroblast growth factor). The mutations that cause ADHR occur in either of two arginine residues in an RXXR motif. This motif is the site for cleavage of FGF23 by a protease of the prohormone convertase class. FGF23 accumulates in patients with ADHR because its clearance by proteolytic degradation is impaired.

  • ARHR is produced by mutations in DMP1 (dentin matrix protein 1) gene, which encodes a noncollagenous bone matrix protein. DMP1, is a member of the SIBLING (Small Integrin‐Binding LIgand N‐linked Glycoprotein) family of secreted acidic extracellular glycophosphoproteins highly expressed in mineralized tissues, specially in osteocytes.

  • Intact plasma levels of the phosphatonin FGF23 are elevated in patients with ARHR, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)(2)D levels found in this disease, and suggesting that DMP1 may regulate FGF23 expression.

  • DMP1 has multiple roles in the regulation of postnatal mineralization through direct effects on mineral formation and crystal growth, and indirect effects on Ca×P concentrations and bone matrix turnover.

  • HHRH is distinct from other forms of hypophosphataemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25‐dihydroxyvitamin D levels and increased intestinal calcium absorption.

  • HHRH was mapped to a 1.6‐Mbp region on chromosome 9q34, which contains SLC34A3, the gene encoding the renal sodium‐phosphate cotransporter NaPi‐IIc. NaPi‐IIc has a key role in the regulation of phosphate homeostasis in the proximal tubule.

Keywords: hypophosphataemia; hereditary hypophosphataemic rickets; FGF23‐sodium‐phosphate cotransporter Iic; PHEX

References

Beck L, Karaplis AC, Amizuka N et al. (1998) Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proceedings of the National Academy of Sciences of the USA 95(9): 5372–5377.

Bergwitz C, Roslin NM, Tieder M et al. (2006) 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. American Journal of Human Genetics 78(2): 179–192.

Berndt T, Craig TA, Bowe AE et al. (2003) Secreted frizzled‐related protein 4 is a potent tumor‐derived phosphaturic agent. Journal of Clinical Investigation 112(5): 785–794.

Bianchine JW, Stambler AA and Harrison HE (1971) Familial hypophosphatemic rickets showing autosomal dominant inheritance. Birth Defects Original Article Series 7(6): 287–295.

Bowe AE, Finnegan R, Jan de Beur SM et al. (2001) FGF‐23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochemical and Biophysical Research Communications 284(4): 977–981.

David L, Pesso JL, Cochat P, Plauchu H and Francois R (1987) Rachitisme hypophosphatémique autosomique type Scriver: Une observation familiale. Pédiatrie 42: 563–568.

DiMeglio LA, White KE and Econs MJ (2000) Disorders of phosphate metabolism. Endocrinology and Metabolism Clinics of North America 29(3): 591–609.

Econs MJ and McEnery PT (1997) Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate wasting disorder. The Journal of Clinical Endocrinology and Metabolism 8: 674–681.

Feng JQ, Ward LM, Liu S et al. (2006) Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nature Genetics 38(11): 1310–1315.

Forster IC, Hernando N, Biber J and Murer H (2006) Proximal tubular handling of phosphate: a molecular perspective. Kidney International 70(9): 1548–1559.

Hardy DC, Murphy WA, Siegel BA, Reid IR and Whyte MP (1989) X‐linked hypophosphatemia: prevalence of skeletal radiographic and scintigraphic features. Radiology 171: 403–414.

HYP consortium (1995) A gene (PEX) with homologies to endopeptidases is mutated in patients with X‐linked hypophosphatemic rickets. Nature Genetics 11: 130–136.

Ichikawa S, Sorenson AH, Imel EA et al. (2006) Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria. The Journal of Clinical Endocrinology and Metabolism 91(10): 4022–4027.

Jain A, Fedarko NS, Collins MT et al. (2004) Serum levels of matrix extracellular phosphoglycoprotein (MEPE) in normal humans correlate with serum phosphorus, parathyroid hormone and bone mineral density. The Journal of Clinical Endocrinology and Metabolism 89(8): 4158–4161.

Ling Y, Rios HF, Myers ER et al. (2005) DMP1 depletion decreases bone mineralization in vivo: an FTIR imaging analysis. Journal of Bone and Mineral Research 20(12): 2169–2177.

Lipman ML, Panda D, Bennett HPJ et al. (1998) Cloning of human PEX cDNA. Expresssion, subcelular localization nad endopeptidase activity. Journal of Biological Chemistry 273: 13729.

Liu S, Rowe PS, Vierthaler L, Zhou J and Quarles LD (2007) Phosphorylated acidic serine‐aspartate‐rich MEPE‐associated motif peptide from matrix extracellular phosphoglycoprotein inhibits phosphate regulating gene with homologies to endopeptidases on the X‐chromosome enzyme activity. Journal of Endocrinology 192(1): 261–267.

Lorenz‐Depiereux B, Bastepe M, Benet‐Pages A et al. (2006a) DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nature Genetics 38(11): 1248–1250.

Lorenz‐Depiereux B, Benet Pages A, Eckstein G et al. (2006b) Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium‐phosphate cotransporter SLC34A3. American Journal of Human Genetics 78(2): 193–201.

Machler M, Frey D, Gal A et al. (1986) X‐linked dominant hypophosphatemia is closely linked to DNA markers DXS41 and DXS43 at XCp22. Human Genetics 73: 271–275.

Madjdpour C, Bacic D, Kassiling B, Murer H and Biber J (2004) Segment‐specific expression of sodium‐phosphate cotransporters NaPi‐IIa and ‐IIc and interacting proteins in mouse renal proximal tubules. Pflugers Archive 448(4): 402–410.

Meyer RA Jr, Meyer MH and Gray RW (1989) Parabiosis suggests a humoral factor is involved in X‐linked hypophosphatemia in mice. Journal of Bone and Mineral Research 4(4): 493–500.

Murer H, Hernando N, Forster I and Biber J (2001) Molecular aspects in the regulation in inorganic phosphate reabsorption: the type IIa sodium/inorganic phosphate cotransporter as the key player. Current Opinion in Nephrology and Hypertension 10: 555–561.

Nesbitt T, Coffman TM, Griffiths R and Drezner MK (1992) Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect. Journal of Clinical Investigation 89(5): 1453–1459.

Polisson RP, Martinez S, Khoury M et al. (1985) Calcifications of entheses associated with X‐linked hypophosphatemic osteomalacia. The New England Journal of Medicine 313: 1–6.

Prié D, Huart V, Bakouh N et al. (2002) Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium‐phosphate cotransporter. The New England Journal of Medicine 347(13): 983–991.

Quarles LD (2003) Evidence for a bone‐kidney axis regulating phosphate homeostasis. Journal of Clinical Investigation 112(5): 642–646.

Reid IR, Hardy DC, Murphy WA et al. (1989) X‐linked hypophosphatemia: a clinical, biochemical and histopatologic assessment of morbidity in adults. Medicine 68: 336–352.

Reid IR, Murphy WA, Hardy DC et al. (1991) X‐linked hypophosphatemia: skeletal mass in adults assessed by histomorphometry, computed tomography and absorptiometry. American Journal of Medicine 90: 63–69.

Rowe PS, Kumagai Y, Gutierrez G et al. (2004) MEPE has the properties of an osteoblastic phosphatonin and minhibin. Bone 34(2): 303–319.

Rowe PSN, Oudet CL, Francis F et al. (1997) PEX mutations in families with X‐linked hypophosphatemic rickets. Human Molecular Genetics 6: 539–549.

Ruchon AF, Marcinkiewwicz M, Siegfried G et al. (1998) Pex mRNA is localized in developing mouse osteoblasts and odontoblasts. The Journal of Histochemistry and Cytochemistry 46: 459–468.

Saito H, Kusano K, Kinosaki M et al. (2003) Human fibroblast growth factor‐23 mutants suppress Na+‐dependent phosphate cotransport activity and 1alpha,25‐dihydroxyvitamin D3 production. Journalc of Biological Chemistry 278(4): 2206–2211.

Scriver CR, MacDonald W, Reade T, Glorieux FH and Nogrady B (1977) Hypophosphatemic nonrachitic bone disease: an entity distinct from X‐linked hypophophatemia in the renal defect, bone involvement, and inheritance. American Journal of Medicinal Genetics 1: 101–117.

Shimada T, Hasegawa H, Yamazaki Y et al. (2004a) FGF‐23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. Journal of Bone and Mineral Research 19(3): 429–435.

Shimada T, Kakitani M, Yamazaki Y et al. (2004b) Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. Journal of Clinical Investigation 113(4): 561–568.

Shimada T, Mizutani S, Muto T et al. (2001) Cloning and characterization of FGF23 as a causative factor of tumor‐induced osteomalacia. Proceedings of the National Academy of Sciences of the USA 98(11): 6500–6505.

Tieder M, Modai D, Samuel R et al. (1985) Hereditary hypophosphatemic rickets with hypercalciuria. The New England Journal of Medicine 312: 611–616.

Toyosawa S, Shintani S, Fujiwara T et al. (2001) Dentin matrix protein 1 is predominantly expressed in chicken and rat osteocytes but not in osteoblasts. Journal of Bone and Mineral Research 16(11): 2017–2026.

Vera CI, Curo JK, Naso WB et al. (1997) Paraplegia due to ossification of Ligamenta flava in X‐linked hypophopsphatemia. Spine 22: 710.

White KE, Evans WE, O'Riordan JL et al. (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. The ADHR Consortium. Nature Genetics 26(3): 345–348.

White KE, Jonsson KB, Carn G et al. (2001) The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting. The Journal of Clinical Endocrinology and Metabolism 86(2): 497–500.

Winters RW, Graham JB, Williams TF, Falls MC and Burnett CHH (1958) A genetic study of familial hypophosphatemia and vitamin D‐resistant rickets with review of the literature. Medicine 37: 97–142.

Yamashita T, Konishi M, Miyake A, Inui K and Itoh N (2002) Fibroblast growth factor (FGF)‐23 inhibits renal phosphate reabsorption by activation of the mitogen‐activated protein kinase pathway. Journal of Biological Chemistry 277(31): 28265–28270.

Futher Reading

Fukumoto S (2008) Physiological regulation and disorders of phosphate metabolism – pivotal role of fibroblast growth factor 23. Internal Medicine 47(5): 337–343.

Imel EA, Hui SL and Econs MJ (2007) FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. Journal of Bone and Mineral Research 22(4): 520–526.

Liu S, Zhou J, Tang W et al. (2006) Pathogenic role of Fgf23 in Hyp mice. American Journal of Physiology. Endocrinology and Metabolism 291(1): E38–E49.

Qin C, D'Souza R and Feng JQ (2007) Dentin matrix protein 1 (DMP1): new and important roles for biomineralization and phosphate homeostasis. Journal of Dental Research 86(12): 1134–1141.

Yamamoto T, Michigami T and Aranami F (2007) Hereditary hypophosphatemic rickets with hypercalciuria: a study for the phosphate transporter gene type IIc and osteoblastic function. Journal of Bone and Mineral Metabolism 25(6): 407–413.

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Negri, Armando Luis(Dec 2008) Molecular Genetics of Inherited Hypophosphataemias. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021465]