Abstract
Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.
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Acknowledgements
We thank the families for participation in this study. We also thank S. Lösecke for technical assistance and H. Murdock, T. Neuhaus, M. Seton and G. El-Hajj Fuleihan for their help in collecting DNA samples. This work was supported by a grant of the Deutsche Forschungsgemeinschaft (STR304/2-2) and the National Institutes of Health (R21 DK075856-01) and in part by the Fondo de Investigación Sanitaria (FIS) of the Spanish Ministry of Health (Research Network Programs C03/07 and G03/097) and the European Foundation for the Study of Diabetes.
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Supplementary information
Supplementary Fig. 1
Mutation analysis of DMP1. (PDF 24 kb)
Supplementary Fig. 2
Expression of DMP1 and in vitro analysis of a possible interaction between DMP1/Dmp1 and PHEX. (PDF 114 kb)
Supplementary Fig. 3
Radiographs of individuals from families 1, 2 and 3. (PDF 2494 kb)
Supplementary Table 1
Sequence variations in the DMP1 and DSPP genes. (PDF 11 kb)
Supplementary Table 2
Chemical data from heterozygous individuals. (PDF 18 kb)
Supplementary Table 3
Morphometric parameters of the iliac bone biopsy specimen obtained from individual 8 in family 3, compared with parameters from an individual of similar age diagnosed with XLH. (PDF 38 kb)
Supplementary Table 4
PCR and sequencing primers. (PDF 18 kb)
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Lorenz-Depiereux, B., Bastepe, M., Benet-Pagès, A. et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 38, 1248–1250 (2006). https://doi.org/10.1038/ng1868
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DOI: https://doi.org/10.1038/ng1868
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