DMP1 – Autosomal Recessive Hypophosphatemic Rickets

Autosomal recessive hypophosphatemic rickets (ARHR) is characterized by renal phosphate wasting, hypophosphatemia, normal serum calcium, and low 1,25-dihydroxyvitamin D. Dentin matrix protein 1 (DMP1) is an acidic extracellular matrix protein essential for bone mineralization and phosphate homeostasis (PMID:18037646). Loss-of-function variants in DMP1 disrupt phosphate regulation via fibroblast growth factor 23 (FGF23) up-regulation.

Genetic Evidence: A novel homozygous nonsense variant c.98G>A (p.Trp33Ter) was identified in two ARHR-affected siblings from a consanguineous Japanese family, with unaffected relatives heterozygous for the allele (PMID:20213538). A second kindred harbored biallelic large deletions and the Met1Val initiation codon variant, both leading to truncated DMP1 and elevated serum FGF23 (PMID:19007919).

In a cohort of 46 families with hypophosphatemic rickets, DMP1 variants were absent in 27 kindreds with PHEX and FGF23 mutations, underscoring the rarity of ARHR and the specificity of DMP1 loss-of-function in the recessive form (PMID:21050253).

Variant Spectrum & Segregation: Reported DMP1 variants include nonsense (e.g., c.98G>A (p.Trp33Ter)), splice-site, and large genomic deletions. No recurrent or founder alleles have been described. Segregation of homozygous LoF alleles with ARHR in two unrelated families provides strong genetic linkage.

Mechanism of Pathogenicity: Truncating DMP1 variants prevent secretion and proteolytic processing into active fragments. A transgenic mouse expressing a cleavage-resistant DMP1(D213A) mutant failed to rescue osteomalacia of Dmp1 knockout mice, demonstrating that proteolytic activation is essential for DMP1 function (PMID:20663874).

Animal Models: Transgenic mice expressing the human c.1484_1490del mutant in a Dmp1-null background displayed tooth hypomineralization and phosphate wasting similar to ARHR patients, confirming in vivo pathogenicity (PMID:20499360).

Conclusion: Biallelic loss-of-function DMP1 variants in at least two unrelated families, segregation data, and concordant in vitro and in vivo functional assays support a Moderate level of gene–disease association. ARHR due to DMP1 mutations should be considered in patients with hypophosphatemia, renal phosphate wasting, elevated FGF23, and normal calcium homeostasis.

References

• Journal of bone and mineral metabolism • 2010 • A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets. PMID:20213538
• Bone • 2009 • Molecular analysis of DMP1 mutants causing autosomal recessive hypophosphatemic rickets. PMID:19007919
• Clinical endocrinology • 2011 • Mutational analysis of PHEX, FGF23 and DMP1 in a cohort of patients with hypophosphatemic rickets. PMID:21050253
• The Journal of biological chemistry • 2010 • Failure to process dentin matrix protein 1 (DMP1) into fragments leads to its loss of function in osteogenesis. PMID:20663874
• Journal of bone and mineral research • 2010 • DMP1 C-terminal mutant mice recapture the human ARHR tooth phenotype. PMID:20499360
• Journal of dental research • 2007 • Dentin matrix protein 1 (DMP1): new and important roles for biomineralization and phosphate homeostasis. PMID:18037646

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