A Novel Recessive Mutation of Fibroblast Growth Factor-23 in Tumoral Calcinosis

Department of Internal Medicine, University Hospital of Florence, Florence, Italy.
The Journal of Bone and Joint Surgery (Impact Factor: 5.28). 06/2009; 91(5):1190-8. DOI: 10.2106/JBJS.H.00783
Source: PubMed


Tumoral calcinosis is a rare disease characterized by hyperphosphatemia due to hypophosphaturia and by ectopic calcifications. Phosphatonins are important hormones that regulate phosphorus homeostasis. Tumoral calcinosis is a rare congenital disorder in which the differential diagnosis from other syndromes associated with extraskeletal calcifications may be difficult. Mutations in the UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase-3 (GALNT3) and fibroblast growth factor-23 (FGF23) genes have been described. Mutational analysis is important for the early recognition of the disorder, for prevention of its complications, and for family screening strategies. We examined two unrelated white patients affected by tumoral calcinosis.
The first patient was a woman with a history of an ectopic calcification in the left shoulder. The second patient was a man with a history of an ectopic calcification in the right buttock. Routine biochemistry and FGF-23 assays were performed on serum samples. Genomic DNA was extracted from peripheral blood. The FGF23 and GALNT3 genes were analyzed by direct sequencing.
A new homozygous H41Q codon 41, C-->A transversion at position 123 (c.123C>A) in exon 1 of the FGF23 gene was evidenced in both patients. No mutation of the GALNT3 gene was detected in these patients. As determined by an ELISA assay, intact FGF-23 circulating protein was low in both patients.
This is the fourth mutation of the FGF23 gene described in subjects with tumoral calcinosis.

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    • "Assessment of HFTC patients without GALNT3 mutations revealed that while dominant gain-of-function mutations in FGF23 result in hypophosphatemic rickets, recessive loss-offunction mutations in the same gene cause HFTC (Araya et al., 2005; Benet-Pages et al., 2005; Chefetz et al., 2005; Larsson et al., 2005b; Lammoglia and Mericq, 2009; Masi et al., 2009). HFTC-causing mutations in FGF23 are associated with a variety of biochemical abnormalities such as abnormal secretion of the intact molecule from the Golgi (Benet- Pages et al., 2005) and decreased FGF23 stability (Larsson et al., 2005a; Garringer et al., 2008). "
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    ABSTRACT: Familial tumoral calcinosis (FTC) refers to a heterogeneous group of inherited disorders characterized by the occurrence of cutaneous and subcutaneous calcified masses. Two major forms of the disease are now recognized. Hyperphosphatemic FTC has been shown to result from mutations in three genes: fibroblast growth factor-23 (FGF23), coding for a potent phosphaturic protein, KL encoding Klotho, which serves as a co-receptor for FGF23, and GALNT3, which encodes a glycosyltransferase responsible for FGF23 O-glycosylation; defective function of any one of these three proteins results in hyperphosphatemia and ectopic calcification. The second form of the disease is characterized by absence of metabolic abnormalities, and is, therefore, termed normophosphatemic FTC. This variant was found to be associated with absence of functional SAMD9, a putative tumor suppressor and anti-inflammatory protein. The data gathered through the study of these rare disorders have recently led to the discovery of novel aspects of the pathogenesis of common disorders in humans, underscoring the potential concealed within the study of rare diseases.
    Journal of Investigative Dermatology 10/2009; 130(3):652-60. DOI:10.1038/jid.2009.337 · 7.22 Impact Factor
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    ABSTRACT: Fibroblast growth factor 23 (FGF23) is a hormone required for normal renal phosphate reabsorption. 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>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 wild-type 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 ((176)RXXR(179)/S(180)) 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.
    AJP Endocrinology and Metabolism 09/2008; 295(4):E929-37. DOI:10.1152/ajpendo.90456.2008 · 3.79 Impact Factor
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    ABSTRACT: The human fibroblast growth factor (FGF) family contains 22 proteins that regulate a plethora of physiological processes in both developing and adult organism. The mutations in the FGF genes were not known to play role in human disease until the year 2000, when mutations in FGF23 were found to cause hypophosphatemic rickets. Nine years later, seven FGFs have been associated with human disorders. These include FGF3 in Michel aplasia; FGF8 in cleft lip/palate and in hypogonadotropic hypogonadism; FGF9 in carcinoma; FGF10 in the lacrimal/salivary glands aplasia, and lacrimo-auriculo-dento-digital syndrome; FGF14 in spinocerebellar ataxia; FGF20 in Parkinson disease; and FGF23 in tumoral calcinosis and hypophosphatemic rickets. The heterogeneity in the functional consequences of FGF mutations, the modes of inheritance, pattern of involved tissues/organs, and effects in different developmental stages provide fascinating insights into the physiology of the FGF signaling system. We review the current knowledge about the molecular pathology of the FGF family.
    Human Mutation 09/2009; 30(9):1245-55. DOI:10.1002/humu.21067 · 5.14 Impact Factor
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