DMP1 Mutations: Another Cause of Hypophosphatemic Rickets

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Hypophosphatemic rickets typically presents in infancy with progressive lower limb deformity and growth deficiency. At least 3 genetically different forms have been identified. The most common X-linked dominant form ([XLH], OMIM 307800) results from inactivating mutations of the phosphate-regulating endopeptidase known as PHEX. Although the molecular pathogenesis of this form is not fully understood, one consequence of the loss of PHEX function is an increase in fibroblast growth factor 23 (FGF23) which directly inhibits renal phosphate reabsorption. Mutations of FGFR3 that interfere with its degradation cause the much less common autosomal dominant form of hypophosphatemic rickets ([ADHR], OMIM 193100). Two groups now report that mutations of the gene encoding dentin matrix protein 1 (DMT1) lead to an autosomal recessive form of hypophosphatemic rickets.

Lorenz-Depiereux et al studied 3 families with clinical features typical of XLH and ADHR, but which displayed autosomal recessive inheritance. Genome-wide linkage analysis led them to a 4.6-Mb region of chromosome 4q21 that contained a cluster of genes encoding a class of tooth and bone noncollagenous matrix proteins referred to as SIBLING ( small integrin- binding ligand, N-linked glycoproteins) proteins. Members of this protein family including dentin, sialophosphoprotein, DMP1, integrin-binding sialoprotein, matrix extracellular phosphoglycoprotein, and osteopontin are thought to function in the mineralization of osteoid and dentin. Direct sequencing of these candidate genes identified mutations that were predicted to cause loss of function of DMP1 in affected individuals of all 3 families. Elevated levels of serum FGF23 were detected in 6 affected family members.

Investigating 2 consanguineous and unrelated families with similar clinical findings, Feng et al detected 2 additional loss-of-function mutations of DMP1. In patients, as well as in mice null for Dmp1, they documented osteomalacia with isolated phosphate-wasting, elevated FGF23 and normocalcuria. In the mutant mice, they demonstrated defective osteocyte maturation and increased expression of the FGF23 gene in bone.

In an accompanying editorial, Schiavi suggested that DMP1 plays multiple roles in regulating mineral metabolism. In skeletal tissues, DMP1, which contains multiple calcium binding sites, may promote extracellular matrix mineralization by nucleating the formation of hydroxyapatite crystals. Accordingly, absence of DMP1 would be expected to cause osteomalacia. However, it has been reported that nonphosphorylated cytoplasmic DMP1 is translocated to the nucleus where it may influence transcription of genes involved in osteoblast differentiation (Figure). Although the mechanism is not known, DMP1 also increases expression of FGF23. Potential roles of DMP1 are depicted schematically in the Figure from this editorial.

Lorenz-Depiereux B, Bastepe M, Benet-Pages A, et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet. 2006;38:1248-50.

Feng JQ, Ward LM, Liu S, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006;38:1310-5.

Editor’s Comment

The extracellular matrix was once considered to be a rather uninteresting, inert substance whose primary function was simply to occupy space between cells. It is becoming clear, however, that matrix proteins play important regulatory roles in many tissues, and disturbances of these roles may underlie disease. A good example is fibrillin-1, which appears to regulate the local availability and accessibility of members of TFG-ß super family of growth factors; disturbances of these functions contribute to the pathogenesis of the Marfan syndrome. DMP1 appears to play a similar role in regulating bone and mineral metabolism.

William A. Horton, MD

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Last Updated: 04/30/2008