We previously demonstrated that the mutations Met1Val (M1V) and the deletion of 
nucleotides 1484-1490 (1484-1490del) in Dentin matrix protein-1 (DMP1) cause the 
novel disorder autosomal recessive hypophosphatemic rickets (ARHR), which is 
associated with elevated fibroblast growth factor-23 (FGF23). To further 
understand the role of DMP1 in ARHR, we undertook molecular genetic and in vitro 
expression studies. First, we examined a kindred with a severe hypophosphatemic 
rickets phenotype and recessive inheritance. Analyses of this family 
demonstrated that the affected members had elevated serum FGF23 and carried a 
large, biallelic deletion that removed the majority of DMP1. At a minimum, this 
deletion encompassed 49 kb between DMP1 exon 3 and an intergenic region 5' to 
the next telomeric gene, integrin-binding sialoprotein (IBSP). We next performed 
immunofluorescent studies in cells to understand the effects of the known ARHR 
mutations on DMP1 cellular processing. These analyses showed that the M1V DMP1 
mutant was not sorted to the trans-Golgi network (TGN) and secretory pathway, 
but filled the entire cytoplasm. In contrast, the 1484-1490del mutant localized 
to the TGN and was secreted, similar to wild type DMP1. The 1484-1490del 
mutation replaces the DMP1 18 C-terminal amino acids with 33 non-native 
residues. Truncation of wild type DMP1 by these native 18 residues followed by 
Western blot and confocal microscopic analyses demonstrated a wild type 
expression pattern when compared with the 1484-1490del mutant, indicating that 
the last 18 residues are not critical for cellular trafficking, but that the 33 
additional residues arising from the 1484-1490del mutation likely compromise 
DMP1 processing. The relationship between DMP1 and FGF23 is unclear. To test 
endogenous DMP1 response to serum metabolites that also regulate FGF23, UMR-106 
cells were treated with 1,25(OH)(2) vitamin D (1x10(-7) M) and showed a 12-fold 
increase in DMP1 mRNA and protein at 24 h. In summary, we have identified a 
novel DMP1 deletion as the cause of ARHR, as well as demonstrated that the ARHR 
mutations alter DMP1 cellular processing, and that DMP1 can be regulated by 
vitamin D. Taken together, this work expands our understanding of the genetic 
and molecular mechanisms associated with DMP1 alterations causing ARHR.