Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred

Specktor, Polina; Cooper, John G.; Indelman, Margarita; Sprecher, Eli

doi:10.1007/s10038-006-0377-6

Cited by 77 publications

(40 citation statements)

References 22 publications

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“…In parallel with the FGF23 mutations, the known GALNT3 inactivating mutations that result in TC lead to decreased stability of full-length, biologically active FGF23 as the molecular pathogenesis of this disorder (5,9,13,29). To date, all patients with FGF23 or GALNT3 mutations share similar COOH-terminal and intact FGF23 ELISA profiles (10).…”

Section: Discussionmentioning

confidence: 99%

Molecular genetic and biochemical analyses of FGF23 mutations in familial tumoral calcinosis

Garringer

Malekpour

Esteghamat

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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FGF23 gain-of-function mutations result in autosomal dominant hypophosphatemic rickets (ADHR), and FGF23 loss-of-function mutations cause familial hyperphosphatemic tumoral calcinosis (TC). In this study, we identified a novel recessive FGF23 TC mutation, a lysine (K) substitution for glutamine (Q) (160 C Ͼ A) at residue 54 (Q54K). To understand the molecular consequences of all known FGF23-TC mutants (H41Q, S71G, M96T, S129F, and Q54K), these proteins were stably expressed in vitro. Western analyses revealed minimal amounts of secreted intact protein for all mutants, and ELISA analyses demonstrated high levels of secreted COOH-terminal FGF23 fragments but low amounts of intact protein, consistent with TC patients' FGF23 serum profiles. Mutant protein function was tested and showed residual, yet decreased, bioactivity compared with wildtype protein. In examining the role of the FGF23 COOH-terminal tail (residues 180 -251) in protein processing and activity, truncated mutants revealed that the majority of the residues downstream from the known FGF23 SPC protease site (176RXXR179/S180) were not required for protein secretion. However, residues adjacent to the RXXR site (between residues 188 and 202) were required for full bioactivity. In summary, we report a novel TC mutation and demonstrate a common defect of reduced FGF23 stability for all known FGF23-TC mutants. Finally, the majority of the COOH-terminal tail of FGF23 is not required for protein secretion but is required for full bioactivity. fibroblast growth factor 23; phosphate; hyperphosphatemia; Klotho PROPER CONTROL OF SERUM PHOSPHATE CONCENTRATIONS is required for normal bone structure and function. Complex endocrine interactions maintain serum phosphate within a relatively narrow range (2.7-4.5 mg/dl in adults) (12,28). The disruption of these regulatory pathways can lead to reciprocal human disorders of hyper-and hypophosphatemia, including familial tumoral calcinosis (TC; OMIM 211900) and autosomal dominant hypophosphatemic rickets (ADHR; OMIM 193100), respectively.The autosomal recessive disorder, TC, is characterized by hyperphosphatemia secondary to increased renal phosphate reabsorption, normal or elevated 1,25(OH) 2 vitamin D concentrations, and normocalcemia (16,24,25). Persistent hyperphosphatemia can result in the development of severe ectopic and vascular calcifications in these patients (16,24,25). Mutations responsible for familial TC were first reported in the GalNac transferase-3 (GALNT3) gene (30). GALNT3 is a UDP-Nacetyl-␣-D-galactosamine:polypeptide N-acetylgalactosaminyl transferase that initiates mucin-like O-linked glycosylation of nascent proteins within the trans-Golgi network (4). Subsequently, we (22) and others (2, 3, 6) have shown that homozygous missense mutations in the fibroblast growth factor 23 (FGF23) gene cause TC; however, whether a common disease mechanism underlies these mutants is unknown.Of significance, patients with TC display clinical findings similar to those found in Fgf23-and Klotho (KL)-null mice (19,26). ␣-...

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Section: Discussionmentioning

confidence: 99%

Molecular genetic and biochemical analyses of FGF23 mutations in familial tumoral calcinosis

Garringer

Malekpour

Esteghamat

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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“…Tumoral calcinosis is caused by biallelic mutations of the genes that encode either FGF23 (28,70) or GalNAc transferase 3 (GALNT3) (21,(71)(72)(73)(74). These mutations alter FGF23 metabolism.…”

Section: Hereditary Disordersmentioning

confidence: 99%

How Fibroblast Growth Factor 23 Works

Liu

Quarles

2007

Journal of the American Society of Nephrology

370

341

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There is a discontinuum of hereditary and acquired disorders of phosphate homeostasis that are caused by either high or low circulating levels of the novel phosphaturic hormone fibroblastic growth factor 23 (FGF23). Disorders that are caused by high circulating levels of FGF23 are characterized by hypophosphatemia, decreased production of 1,25-dihydroxyvitamin D, and rickets/osteomalacia. On the other end of the spectrum are disorders that are caused by low circulating levels of FGF23, which are characterized by hyperphosphatemia, elevated production of 1 Fibroblast Growth Factor 23 Gene and Protein StructureThe fibroblast growth factor (FGF) family consists of 22 members with varied functions (2). FGF23 is an approximately 32-kD (251 amino acids) protein with an N-terminal region that contains the FGF homology domain and a novel 71-amino acid C-terminus that was originally discovered by homology-based PCR screening of a mouse embryonic cDNA library (3). The FGF23 gene is located on Chr 12p13 and is phylogenetically grouped with FGF19 and 21 gene products (2,3), with which it has approximately 24% and approximately 22% amino acid identities, respectively. FGF23 principally acts as a phosphaturic factor and suppressor of 1␣-hydroxylase activity in the kidney (4,5), making it functionally distinct from other members of this family. Tissue Expression and Function: Evidence for a Bone-Kidney AxisFGF23 is predominately expressed in osteocytes in bone (6,7), but it is also expressed in pericyte-like cells that surround the venous sinuses in the bone marrow, in the ventrolateral thalamic nucleus, and in thymus and lymph nodes (Figure 1). The relative contribution of these sites to circulating FGF23 levels is not known, but the high levels of expression in the osteocyte and that osteocytes are the most abundant cell in bone suggest that the serum levels of FGF23 are derived mainly from bone. In addition, the production of FGF23 by osteocytes, cells that are central to the regulation of osteoblast function and mineralization, likely has functional significance (8). In this regard, osteocytes secrete sclerostin, an inhibitor of bone formation and the phosphaturic factor FGF23, as well as other gene products, such as phosphate-regulating endopeptidase homolog, X-linked (Phex), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE), that regulate bone mineralization and FGF23 expression. Phex is a type I cell surface zinc metalloprotease that is involved in the regulation of FGF23 levels and is mutated in X-linked hypophosphatemic rickets (9). Both DMP1 and MEPE are glycophosphoproteins that belong to the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of proteins. MEPE and DMP1 are predominately expressed in bones and/or teeth, where they respectively inhibit and induce mineralization of extracellular matrix (10). These associations suggest that osteocytes coordinate osteoblast-mediated bone formation with renal regulation of systemic phosphate homeostasis through the regu...

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“…Previous molecular genetic analyses demonstrated that tumoral calcinosis can result from biallelic inactivating mutations in genes encoding FGF23 (1)(2)(3)(4) or the UDP-N-acetyl-α-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) (5)(6)(7)(8). FGF23 is a hormone that promotes renal phosphate excretion by decreasing phosphate reabsorption in the proximal tubule and also reduces circulating 1,25(OH) 2 D by both decreasing biosynthesis and increasing metabolism of 1,25(OH) 2 D (9).…”

Section: Introductionmentioning

confidence: 99%