Despite its demonstrated broad importance, the regulation of phosphate homeostasis remains incompletely understood. With the exception of cDNAs encoding different sodium-phosphate co-transporters, all molecules thus far known to be involved in regulating phosphate homeostasis have been identified by defining the molecular basis of different hereditary disorders in humans and mice that are characterized by an abnormal regulation of phosphate homeostasis. These studies by different groups have led to the identification of key regulators, including 1) PHEX, which is mutated in X-linked hypophosphatemia (XLH), 2) FGF23, for which gain-of-function mutations were found in autosomal dominant hypophosphatemic rickets (ADHR) and loss-of-function mutations in a form of familial tumoral calcinosis (FTC-2), and 3) GALNT3, an enzyme important for the initiation of O-linked glycosylation, for which loss-of-function mutations were identified in another familial form of tumoral calcinosis (FTC-1). Using the assay that was developed in our laboratory, loss of function mutations in either FGF23 or GALNT3 were shown to be associated with a dramatic increase in the serum concentration of C-terminal FGF23, yet normal intact FGF23 levels. These findings indicated that FGF23 requires post-translational modifications for normal intracellular processing and possibly for mediating its actions through some of the known FGF receptors that may recruit Klotho as a co-receptor. Using a positional cloning strategy, we recently identified NaPi-llc mutations as the cause of hereditary hypophosphatemic rickets with hypercalciuria (HHRH), thereby providing first evidence for the conclusion that NaPi-llc has a major role in renal phosphate handling. However, despite these advances in the identification of key regulators of phosphate homeostasis, it remains largely uncertain how and to what extent the identified proteins contribute to the regulation of phosphate homeostasis, and it is very likely that additional proteins are involved in these regulatory mechanisms. To explore the biology of phosphate homeostasis further, we now propose to identify a novel regulator of phosphate homeostasis by searching for the molecular defect leading to an autosomal recessive phosphate-wasting disorder that is associated with osteosclerosis. We mapped this disorder to chromosome 4q21, and once the disease-causing genetic mutation is known, we will begin exploring the underlying pathophysiological mechanisms leading to phosphate-wasting and osteosclerosis. Furthermore, we will determine whether the HPOS gene product has a role in the regulation of phosphate homeostasis in healthy individuals. In addition to defining a rare genetic disorder, these efforts may provide novel therapeutic approaches for the treatment of more common hypo- and hyperphosphatemic conditions that also affect bone metabolism, such as X-linked hypophosphatemia (XLH) and chronic kidney disease (CDK), respectively. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK075856-01
Application #
7133263
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Rasooly, Rebekah S
Project Start
2006-08-10
Project End
2008-05-31
Budget Start
2006-08-10
Budget End
2007-05-31
Support Year
1
Fiscal Year
2006
Total Cost
$262,500
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Mäkitie, Outi; Pereira, Renata C; Kaitila, Ilkka et al. (2010) Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation. J Bone Miner Res 25:2165-74
Turan, Serap; Aydin, Cumhur; Bereket, Abdullah et al. (2010) Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia. Bone 46:402-9
Lorenz-Depiereux, Bettina; Bastepe, Murat; Benet-Pages, Anna et al. (2006) DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 38:1248-50