Clemens Bergwitz, MD

Genetic causes of hypophosphatemia

In 2006 we identified the genetic defect underlying the childhood disorder Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH). HHRH is caused by mutations in NaPi-IIc, a renal sodium-phosphate co-transporter, which is important to conserve phosphate in the kidney and when lost leads to hypophosphatemia and rickets. Our research goal is now to study the role of NaPi-IIc in human phosphate homeostasis and to understand the phenotypic variability of patients suffering from HHRH. For this purpose we are currently using mammalian and Xenopus oocyte expression systems to study the functional properties of the identified human NaPi-IIc mutations in vitro. Plan for the near future is to establish mouse models to study the role of NaPi-IIc in the development of renal stones in vivo. We also established international collaborations to look for NaPi-IIc mutations in new patients suffering from HHRH both to establish their molecular diagnosis and to carefully study their symptoms to see whether only some or all patients are at risk for developing kidney stones. In addition to HHRH I serve as the principal investigator on clinical trials for serveral other genetic skeletal disorders, including X-linked hypophosphatemia, osteogenesis imperfecta and hypophosphatasia.

Metabolic and homeostatic effects of phosphate

A more recent research interest is in trying to understand how human and other metazoan cells sense inorganic phosphate to explain the effects of phosphate on cell metabolism (“metabolic” sensing), how phosphate feeds back to regulate the above hormonal systems (“homeostatic” sensing) and whether the “metabolic” and the “homeostatic” sensor use the same or different signal transduction cascades.

For this purpose we have performed a genome-wide Drosophila RNAi knockdown in collaboration with Stephanie Mohr, Liz Perkins and Norbert Perrimon, Harvard Medical School using phosphate-induced activation of MAPK (in vitro). The identified 103 genes, including 84 phosphate-specific genes are currently evaluated in life flies with assays for dietary phosphate toxicity, hemolymph phosphate and life span. Our goal in the next few years will be to identify mammalian systems suitable to study phosphate sensing, while further exploring Drosophila melanogaster as model organism. Relevant readouts for humans will be the homeostatic regulation of synthesis and secretion of PTH, 1,25-D, FGF23 by phosphate and it’s metabolic effects on life-span in genetic disorders such as familial hyperphosphatemic tumoral calcinosis (FHTC) and in chronic kidney disease.