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

Department of Medical and Molecular Genetics (T.L., X.Y., S.I.D., S.D.M., K.E.W.), Indiana University School of Medicine, Indianapolis, Indiana 46202; and Department of Endocrinology (M.S.D., M.J.C.), Saint James’s Hospital and Trinity College Dublin Medical School, Dublin 8, Ireland

Address all correspondence and requests for reprints to: Kenneth E. White, 975 West Walnut Street, IB130, Indianapolis, Indiana 46202. E-mail: kenewhit{at}iupui.edu.

Abstract

Gain-of-function mutations in fibroblast growth factor-23 (FGF23) are responsible for autosomal dominant hypophosphatemic rickets, a disorder of isolated renal phosphate wasting. Patients with the disorder display hypophosphatemia with normocalcemia as well as inappropriately normal 1,25-dihydroxyvitamin D [1,25(OH)₂D₃] concentrations. Reciprocally tumoral calcinosis (TC) patients are often hyperphosphatemic with inappropriately normal or elevated serum 1,25(OH)₂D₃ levels and have ectopic and vascular calcifications, a phenotype similar to that of Fgf23 null mice. Therefore, the goal of the present studies was to test whether FGF23 was a candidate gene for TC. Two sisters in a consanguineous TC family had hyperphosphatemia and normal 1,25(OH)₂D₃ levels with characteristic ectopic and vascular calcifications. Interestingly, these patients had low-normal intact serum FGF23 levels but demonstrated FGF23 concentrations approximately 40 times normal when assessed with a C-terminal FGF23 serum assay. Mutational analyses identified a homozygous S71G mutation in FGF23 in the TC patients, which was not found in control alleles. Finally, modeling demonstrated that the S71G mutation most likely destabilizes full-length FGF23. In summary, recessive FGF23 mutations can lead to TC. Additionally, our findings indicate that FGF23 may adopt an unstable conformation in some TC patients, possibly leading to nonfunctional FGF23 protein.

AUTOSOMAL DOMINANT hypophosphatemic rickets (ADHR) is a heritable disorder arising from missense mutations in fibroblast growth factor (FGF)-23 (1) that stabilize the full-length polypeptide (2). Patients with ADHR share similarities with individuals affected by other heritable disorders of phosphate (Pi) wasting, such as X-linked hypophosphatemia and tumor-induced osteomalacia and thus manifest hypophosphatemia, decreased or inappropriately normal serum 1,25-dihydroxyvitamin D [1,25(OH)₂D₃], and osteomalacia (3, 4). In addition, FGF23 is elevated in many patients with X-linked hypophosphatemia and tumor-induced osteomalacia (5). Conversely, tumoral calcinosis (TC) patients are hyperphosphatemic with elevated or inappropriately normal 1,25(OH)₂D₃ (with regard to the severe hyperphosphatemia) and present with ectopic calcified tumoral masses as well as vascular calcifications (6, 7), a phenotype similar to that described in the Fgf23 knockout mouse (8). Recessive inactivating mutations in GALNT3, the UDP-N-acetyl--D-galactosamine/polypeptide N-acetylgalactosminyl transferase-3 enzyme responsible for initiating mucin-like O-linked glycosylation (9), have recently been associated with familial TC (10). However, the molecular mechanisms underlying the etiology of TC due to the GALNT3 mutations are unknown. Within the current study, we sought to determine whether FGF23 mutations were responsible for TC because of the significant overlaps in biochemical and calcification phenotypes associated with TC patients and the Fgf23 null mouse.

Patients and Methods

Tumoral calcinosis patients

All patients provided written, informed consent in accord with the Institutional Review Board of Indiana University. Routine serum biochemistries were assessed by standard protocols.

FGF23 serum assays

Serum intact FGF23 concentrations were assessed using an ELISA according to the manufacturer’s protocol (Kainos Laboratories International, Tokyo, Japan) (11). Serum FGF23 concentrations were also evaluated using the Immutopics, Inc. (San Clemente, CA) FGF23 serum assay kit according to the manufacturer’s instructions. This kit is a two-site sandwich ELISA-based assay that recognizes the C-terminal portion of FGF23 (5).

FGF23 mutational analysis

Genomic DNA was extracted from blood samples using the Qiamp DNA blood extraction kit (Qiagen, Inc., Valencia, CA) according to the manufacturer’s protocol. The three FGF23 exons, including the intron-exon splice junctions, were PCR amplified with intronic primers (exon 1 forward (F): 5'-aat ctc agc acc agc cac tc-3', reverse (R): 5'-gat gga caa caa ggg tgc tc-3'; exon 2 F: ttt cag gag gtg ctt gaa gg-3', R: 5'-ttg caa atg gtg acc aac ac-3'; and exon 3 F: 5'-ctt cac gtg gtt cgc tct tg-3', R: 5'-tgc tga ggg atg ggt taa ag-3') using 20 ng genomic DNA as templates. PCR conditions for all experiments were as follows: 1 min at 95 C, followed by 35 cycles of 1 min at 95 C, 1 min at 57 C, 1 min at 72 C, and a final extension of 7 min at 72 C. Amplified exons were analyzed by DNA sequencing with the appropriate forward primers for each FGF23 exon using Big Dye terminator chemistry or the [³³P]dideoxy nucleotide triphosphate thermosequenase kit (USB Corp., Cleveland, OH).

Structural analyses

The effects of FGF23 residue substitutions on FGF23 secondary structure were analyzed using SIFT (blocks.fhcrc.org/sift/SIFT.html) and NNPredict software (www.cmpharm.ucsf.edu/~nomi/nnpredict.html).

Results

Phenotypic assessment of TC family

A small Caucasian TC kindred consisting of two affected sisters was previously examined. The affected individuals were found to have hyperphosphatemia secondary to increased percent tubular reabsorption of Pi (TRP 93.8 and 89.6%) and mild hypercalcemia. The patients also presented with calcification of the vertebral disks and soft tissue of the lower limbs. Furthermore, they had placental and femoral artery calcifications, consistent with the diagnosis of TC (12). In the current study, we expanded this kindred’s family tree through detailed family histories, which importantly revealed that the family was consanguineous (Fig. 1).

View larger version (21K): [in this window] [in a new window]   FIG. 1. Family tree of TC family. The affected individuals were the children of second cousins. Arabic numerals indicate the number of children of the same gender.

View larger version (23K): [in this window] [in a new window]   FIG. 2. Serum FGF-23 levels in the proband (dashed bars) and patient 2 (black bars). FGF23 levels were low-normal when measured with the intact assay (left: mean ± SEM; 28.9 ± 1.1) but markedly elevated when measured with the C-terminal assay (right: mean ± SD; 55 ± 50). Mean values for the two assays are indicated by the dashed lines.

On the basis of the disparate findings between the intact and C-terminal FGF23 serum assays as well as the similarity of the hyperphosphatemia and calcification phenotypes shared between this TC family and the Fgf23 null mouse, we tested DNA from the TC kindred and control individuals for FGF23 mutations. We discovered a homozygous S71G (211A>G) substitution in exon 1 of FGF23 in the two affected patients (Fig. 3), which was not found in the single nucleotide polymorphism database (www.ncbi.nlm.nih.gov/SNP/). Moreover, this change was not found in 106 Caucasian control alleles, confirming the substitution as a novel mutation. Furthermore, direct sequencing of the GALNT3 exons revealed no disease-causing mutations (not shown).

View larger version (48K): [in this window] [in a new window]   FIG. 3. S71G TC mutation in FGF23. Sequencing of FGF23 exons revealed a homozygous S71G (211A>G, arrow) change in the proband (top panel) and patient 2 (not shown). The corresponding residue change is shown above the second nucleotide for each codon. This mutation was not found in control individuals (lower panel).

FGF23 structural analyses To determine the effects of the S71G mutation on the mature FGF23 protein product, we used SIFT and NNPredict secondary structure prediction software. After alignment of 27 human, rat, and mouse FGF sequences, SIFT analyses at S71, with a threshold for substitution intolerance of less than 0.05, indicated a deleterious effect on FGF23 structure with the introduction of the Gly residue (intolerance score of 0.01). Mechanistically, the S71G change has the potential to effect FGF23 folding because NNPredict determined that S71 occurs within residues 68–76 that comprise the fourth of the 12 antiparallel ß-strands of FGF23, and when present, the mutation is predicted to disrupt this ß-strand.

Discussion

FGF23 is a critical mediator of Pi and of vitamin D metabolism, as exemplified by the fact that heterozygous FGF23-stabilizing mutations cause the isolated renal Pi wasting disorder ADHR (1). Our present studies demonstrate that recessive FGF23 missense mutations can result in TC, with the opposite phenotype to ADHR, thus involving hyperphosphatemia and inappropriately normal 1,25(OH)₂D₃ concentrations (Table 1). Because our TC patients’ phenotypes also resemble that of Fgf23 null mice, it is a reasonable assumption that the S71G mutation identified herein is an apparent loss of function in FGF23. Several observations support this hypothesis. First, lack of FGF23 would explain the hyperphosphatemia and the inappropriately normal serum levels of 1,25(OH)₂D₃ because introduction of FGF23 in vivo down-regulates Npt2a and the renal 1--hydroxylase proteins, thus reducing serum Pi and 1,25(OH)₂D₃ levels, respectively (14, 15). Second, the low-normal serum PTH levels and mild hypercalcemia seen in our TC patients are observed from 6 wk of age in Fgf23 null mice (8) and are essentially a mirror image to that of several FGF23 transgenic models (16, 17). This may imply that FGF23 has a direct stimulatory effect on parathyroid gland cell proliferation and/or PTH secretion.

Phenotypic differences exist between our TC patients and Fgf23 null mice. These differences include early lethality and growth retardation in the mice and could be due to the presence of some intact circulatory FGF23 in TC patients (Fig. 2), whereas the mice harbor total biallelic Fgf23 gene deletions. Alternatively, the differences may be due to species-specific modifier genes or to yet incompletely understood compensatory mechanisms. Lastly, the S71G mutation is predicted to destabilize the FGF23 protein in sequence modeling, supporting the loss-of-function hypothesis. If FGF23 were destabilized, the mutant protein may be structurally compromised, which could result in overproduction of partially- or nonfunctional FGF23 protein (e.g. C-terminal fragments). Thus, our patients are potentially unable to correctly regulate serum Pi and 1,25(OH)₂D₃, as is the case with the Fgf23 null mouse (8). Alternatively, the elevated C-terminal FGF23 concentrations in our patients may be a feedback response to the prevailing hyperphosphatemia as reported with increased serum Pi levels associated with chronic renal failure (18). The lack of a high reading by the intact FGF23 serum assay could also represent a scenario in which the S71G mutation results in a shortened FGF23 polypeptide with deleted N-terminal residues due to functional consequences of the mutation or to the possibility that a partial unfolding of FGF23 occurs so that the conformation-specific antibodies used in the intact assay do not recognize full-length FGF23. The C-terminal assay would hypothetically still recognize either a shorter FGF23 protein moiety if FGF23 was secreted as a truncated polypeptide or a partially unfolded FGF23 if full-length FGF23 was produced.

It was recently reported that inactivating recessive mutations in GALNT3 cause familial TC (10). GALNT3 encodes a glycosyltransferase responsible for initiating mucin-like O-linked glycosylation (9). The fact that mutations in GALNT3, a glycosylation enzyme, also cause TC leads to the logical hypothesis that there may be a direct substrate-enzyme relationship between FGF23 and GALNT3. Interestingly, the S71G mutation in FGF23 comprises a serine residue, an amino acid that potentially allows O-linked glycosylation. Although more patients need to be examined, a scenario could be envisioned in which the complete lack of glycosylation of FGF23 in the GALNT3-TC patients could result in improper secondary structure of FGF23 and in turn reduced biological activity. On the contrary, in TC patients carrying both S71G mutant alleles, FGF23 may fail to undergo glycosylation specifically at position S71. Indeed, S71G FGF23 could presumably still be glycosylated at other potential O-linked sites, resulting in a less severe change in FGF23 secondary structure. Speculatively, this may lead to a slightly milder ectopic calcification phenotype, as described in our patients (12). In agreement with the 40-fold elevated C-terminal FGF23 concentrations in our TC family (Fig. 2), the reported C-terminal FGF23 values for the GALNT3 patients were approximately 30-fold higher than the mean for control individuals (>1700 RU/ml) (10). Although intact serum FGF23 concentrations were not examined in the GALNT3-TC patients, the marked similarity with our patients’ FGF23 serum profile could imply that O-linked glycosylation may be critical for maintenance of FGF23 secondary structure and biological action. However, because we were unable to establish through known protein databases that S71 comprised a predicted glycosylation site, the possibility of a direct relationship between GALNT3 and FGF23 will need to be further explored. In summary, an S71G recessive mutation in FGF23 causes TC. Understanding the functional significance and molecular physiology of this novel mutation will reveal critical information regarding the role of FGF23 in states of normal and disordered Pi homeostasis.

Acknowledgments

We thank the TC family, Michael J. Econs and Moosa Mohammadi, for their generous scientific support.

Footnotes

This work was supported by National Institutes of Health Grant DK063934 (to K.E.W.) and the Indiana Genomics Initiative, Indiana University, supported in part by Lilly Endowment, Inc.

First Published Online February 1, 2005

¹ T.L. and X.Y. contributed equally to this work.

Abbreviations: ADHR, Autosomal dominant hypophosphatemic rickets; F, forward; FGF, fibroblast growth factor; 1,25(OH)₂D₃, 1,25-dihydroxyvitamin D; Pi, phosphate; R, reverse; TC, tumoral calcinosis.

Received November 15, 2004.

Accepted January 20, 2005.

References

1. ADHR Consortium 2000 Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26:345–348[CrossRef][Medline]
2. White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ 2001 Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int 60:2079–2086[CrossRef][Medline]
3. Tenenhouse HS, Econs MJ 1998 Mendelian hypophosphatemias. In: Scriver CR, ed. The metabolic and molecular basis of inherited disease. New York: McGraw-Hill
4. Econs MJ, McEnery PT 1997 Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab 82:674–681[Abstract/Free Full Text]
5. Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, Yamamoto T, Hampson G, Koshiyama H, Ljunggren O, Oba K, Yang IM, Miyauchi A, Econs MJ, Lavigne J, Juppner H 2003 Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 348:1656–1663[Abstract/Free Full Text]
6. Inclan A, Leon P, Camjeo MG 1943 Tumoral calcinosis. JAMA 121:490–495[Abstract/Free Full Text]
7. Prince MJ, Schaeffer PC, Goldsmith RS, Chausmer AB 1982 Hyperphosphatemic tumoral calcinosis: association with elevation of serum 1,25-dihydroxycholecalciferol concentrations. Ann Intern Med 96:586–591
8. Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T 2004 Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113:561–568[CrossRef][Medline]
9. Bennett EP, Hassan H, Clausen H 1996 cDNA cloning and expression of a novel human UDP-N-acetyl-alpha-D-galactosamine. Polypeptide N-acetylgalactosaminyltransferase, GalNAc-t3. J Biol Chem 271:17006–17012[Abstract/Free Full Text]
10. Topaz O, Shurman DL, Bergman R, Indelman M, Ratajczak P, Mizrachi M, Khamaysi Z, Behar D, Petronius D, Friedman V, Zelikovic I, Raimer S, Metzker A, Richard G, Sprecher E 2004 Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet 36:579–581[CrossRef][Medline]
11. Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, Takeuchi Y, Fujita T, Nakahara K, Yamashita T, Fukumoto S 2002 Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab 87:4957–4960[Abstract/Free Full Text]
12. Li Voon Chong SW, Ah Kion S, Cullen MJ 1999 A report of familial hyperphosphataemia in an Irish family. Ir J Med Sci 168:262–264[Medline]
13. Ornitz DM, Itoh N 2001 Fibroblast growth factors. Genome Biol 2:3005
14. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T 2001 Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 98:6500–6505[Abstract/Free Full Text]
15. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T 2004 FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19:429–435[CrossRef][Medline]
16. Larsson T, Marsell R, Schipani E, Ohlsson C, Ljunggren O, Tenenhouse HS, Juppner H, Jonsson KB 2004 Transgenic mice expressing fibroblast growth factor 23 under the control of the 1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology 145:3087–3094[CrossRef][Medline]
17. Bai X, Miao D, Li J, Goltzman D, Karaplis AC 2004 Transgenic mice overexpressing human fibroblast growth factor 23 (R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders. Endocrinology 145:5269–5279[CrossRef][Medline]
18. Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB 2003 Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int 64:2272–2279[CrossRef][Medline]

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