DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis

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.

Figure 1

DMP1 mutations in three families with autosomal recessive hypophosphatemia. All affected individuals were homozygous for the mutated allele segregating in the corresponding family. The parents were heterozygous for the respective mutation. Affected individuals are indicated by filled symbols and heterozygous carriers by half-filled symbols. Radiographs for affected members of each family are shown in Supplementary Figure 3 online. Morphometric parameters of an iliac bone biopsy specimen from an affected individual in family 3 are shown in Supplementary Table 3 online. Primer sequences used for sequence analysis are listed in Supplementary Table 4 online. Informed consent was obtained from all study participants. The study was approved by the institutional review boards of the Medical Department of the Technical University of Munich and Massachusetts General Hospital.