Human Molecular Genetics Advance Access originally published online on December 8, 2004
Human Molecular Genetics 2005 14(3):385-390; doi:10.1093/hmg/ddi034
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Human Molecular Genetics, Vol. 14, No. 3 © Oxford University Press 2005; all rights reserved
An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia
1Institute of Human Genetics, GSF National Research Center for Environment and Health, Ingolstädter Landstr. 1, 85764 Munich–Neuherberg, Germany, 2Department of Pediatrics, Innsbruck Medical University, Anichstr. 35, 6020 Innsbruck, Austria and 3Institute of Human Genetics, Klinikum rechts der Isar, Technical University, Ismaningerstr. 22, 81675 Munich, Germany
* To whom correspondence should be addressed. Tel: +49 8931873296; Fax: +49 8931873297; Email: timstrom{at}gsf.de
Received October 4, 2004; Revised November 19, 2004; Accepted November 26, 2004
Familial tumoral calcinosis (FTC) is an autosomal recessive disorder characterized by ectopic calcifications and elevated serum phosphate levels. Recently, mutations in the GALNT3 gene have been described to cause FTC. The FTC phenotype is regarded as the metabolic mirror image of hypophosphatemic conditions, where causal mutations are known in genes FGF23 or PHEX. We investigated an individual with FTC who was negative for GALNT3 mutations. Sequencing revealed a homozygous missense mutation in the FGF23 gene (p.S71G) at an amino acid position which is conserved from fish to man. Wild-type FGF23 is secreted as intact protein and processed N-terminal and C-terminal fragments. Expression of the mutated protein in HEK293 cells showed that only the C-terminal fragment is secreted, whereas the intact protein is retained in the Golgi complex. In addition, determination of circulating FGF23 in the affected individual showed a marked increase in the C-terminal fragment. These results suggest that the FGF23 function is decreased by absent or extremely reduced secretion of intact FGF23. We conclude that FGF23 mutations in hypophosphatemic rickets and FTC have opposite effects on phosphate homeostasis.
AY753222 and AY753223.
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