Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, Muller-Barth U et al.DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 38:1248-1250
Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.
"DMP1 is a multifunctional protein involved in the biomineralization of bones and dentin (Ling et al., 2005; Lu et al., 2007; Qin et al., 2004), phosphate homeostasis (Feng et al., 2006), and differentiation of odonto-and osteoblasts (Almushayt et al., 2006; Narayanan et al., 2001). Mutations in this gene cause autosomal recessive hypophosphatemic rickets syndrome , manifested by rickets and osteomalacia with isolated renal phosphate-wasting (Feng et al., 2006; Lorenz-Depiereux et al., 2006). DMP1 belongs to the SIBLING (Small Intergrin Binding Nlinked Glicoproteins) family, which are associated with mineralized tissues (Fisher and Fedarko, 2003), although they were found in other tissues as well (Fisher et al., 2004; Ogbureke and Fisher, 2005). "
"As mentioned above, FGF23 was identified as a responsible gene for ADHR . Furthermore, autosomal recessive hypophosphatemic rickets 1 and 2 (ARHR1, 2) are caused by mutations in dentin matrix protein 1 (DMP1) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), respectively [11,12,13,14]. Mutations in PHEX, DMP1, and ENPP1 in these diseases are considered to be inactivating mutations. "
[Show abstract][Hide abstract] ABSTRACT: Fibroblast growth factor 23 (FGF23) is a hormone that is produced by osteocytes and regulates phosphate and vitamin D metabolism through binding to the Klotho-FGF receptor complex. Excessive actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia. Tumor-induced rickets/osteomalacia (TIO) is a paraneoplastic syndrome caused by overproduction of FGF23 from the responsible tumors. Because TIO is cured by complete resection of the causative tumors, it is of great clinical importance to locate these tumors. Several imaging methods including skeletal survey by magnetic resonance imaging and octreotide scintigraphy have been used to identify the tumors that cause TIO. However, none of these imaging studies indicate that the detected tumors are actually producing FGF23. Recently, systemic venous sampling was conducted for locating FGF23-producing tumor in suspected patients with TIO and demonstrated that this test might be beneficial to a subset of patient. Further studies with more patients are necessary to establish the clinical utility of venous sampling in patients with TIO.
"In hereditary cases, X-linked hypophosphatemic rickets (XLH) with inactivating mutations of the phosphate regulating gene with homologies to endopeptidases (PHEX) gene is the most common . Autosomal dominant hypophosphatemic rickets and autosomal recessive hypophosphatemic rickets have also been reported [3,4]. Acquired hypophosphatemic rickets includes tumor-induced osteomalacia (TIO)  and sporadic hypophosphatemic rickets . "
[Show abstract][Hide abstract] ABSTRACT: Phosphate regulating gene with homologies to endopeptidases on the X-chromosome (PHEX) is a common cause of X-linked hypophosphatemic (XLH) rickets. Diverse PHEX gene mutations have been reported; however, gene mutations in sporadic rickets are less common than in XLH rickets. Herein, we describe a 50-year-old female patient with sporadic hypophosphatemic rickets harboring a novel splicing-site mutation in the PHEX gene (c.663+1G>A) at the exon 5-intron 5 boundary. The patient had recently suffered from right thigh pain and an aggravated waddling gait. She also presented with very short stature, generalized bone pain, and muscle weakness. Despite low serum phosphate levels, her phosphate reabsorption rate was lower than normal. Additionally, her 1,25-dihydroxyvitamin D3 concentration was lower than normal, although FGF23 level was normal. After treatment with alfacalcidol and elemental phosphate, her rachitic symptoms subsided, and callus formation was observed in the fracture site on the right femur.
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