A novel homozygous missense mutation in FGF23 causes Familial Tumoral Calcinosis associated with disseminated visceral calcification

Chefetz, Ilana; Heller, Raoul; Galli-Tsinopoulou, Assimina; Richard, Gabriele; Wollnik, Bernd; Indelman, Margarita; Koerber, Friederike; Topaz, Orit; Bergman, Reuven; Sprecher, Eli; Schöenau, Eckhard

doi:10.1007/s00439-005-0026-8

Cited by 121 publications

(66 citation statements)

References 22 publications

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“…1b). Ophthalmological examination disclosed whitish ''salt-like'' deposits on the conjunctiva as previously described (Chefetz et al 2005). Of note, no cutaneous calcifications were observed.…”

Section: Clinical Findingssupporting

confidence: 71%

“…Although most patients display periarticular calcifications, other manifestations, such as visceral or mucosal involvement, are not invariably seen (Gal et al 1994;Topaz et al 2004;Chefetz et al 2005). Apart from severe joint disease, the present case was remarkable for prominent dental anomalies.…”

Section: Discussionmentioning

confidence: 60%

“…It is often associated with hyperphosphatemia (Smack et al 1996), and is then termed hyperphosphatemic familial tumoral calcinosis (HFTC; MIM211900). HFTC has been shown to result from loss-of-function mutations in at least two genes: GAL-NT3 coding for UDP-N-acetyl-alpha-D-galactosamine: polypeptide n-acetylgalactosaminyltransferase 3 (ppGalNacT3) (Topaz et al 2004;Ichikawa et al 2005), a glycosyltransferase, which initiates O-glycosylation (Ten Hagen et al 2003);and FGF23 (Benet-Page`s et al 2005;Larsson et al 2005;Araya et al 2005;Chefetz et al 2005) coding for fibroblast growth factor 23 (FGF23), a potent phosphaturic protein (Berndt et al 2005).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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Hyperphosphatemic familial tumoral calcinosis (HFTC) is an autosomal recessive metabolic disorder characterized by extensive phenotypic and genetic heterogeneity. HFTC was shown recently to result from mutations in two genes: GALNT3, coding for a glycosyltransferase responsible for initiating O-glycosylation, and FGF23, coding for a potent phosphaturic protein.All GALNT3 mutations reported so far have been identified in patients of either Middle Eastern or African-American extraction, corroborating numerous historical reports of the disorder in Africa and in the Middle East. In the present study, we describe a patient of Northern European origin displaying typical features of HFTC. Mutation analysis revealed that this patient carries a homozygous novel nonsense mutation in GALNT3 predicted to result in the synthesis of a significantly truncated protein. The present results expand the spectrum of known mutations in GALNT3 and demonstrate the existence of HFTC-causing mutations in this gene outside the Middle Eastern and AfricanAmerican populations.

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Section: Clinical Findingssupporting

confidence: 71%

Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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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%

A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis

et al. 2007

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“…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.…”

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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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A novel homozygous missense mutation in FGF23 causes Familial Tumoral Calcinosis associated with disseminated visceral calcification

Cited by 121 publications

References 22 publications

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

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

A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis

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

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