Nephrocalcinosis; Phosphorus Metabolism Disorders; Rickets; Signal Transduction; Phosphate Transport Proteins; Genetic Diseases, Inborn
Public Health Interests
Genetics, Genomics, Epigenetics; Metabolism
Our research focuses on inborn errors of phosphate metabolism and the endocrine regulation of phosphate homeostasis with emphasis on the metabolic and homeostatic effects of phosphate.
Extensive Research Description
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.
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.
Impaired urinary osteopontin excretion in Npt2a-/- mice.
Caballero D, Li Y, Ponsetto J, Zhu C, Bergwitz C. Impaired urinary osteopontin excretion in Npt2a-/- mice. American Journal Of Physiology. Renal Physiology 2017, 312:F77-F83. 2017
Hypophosphatemia promotes lower rates of muscle ATP synthesis.
Pesta DH, Tsirigotis DN, Befroy DE, Caballero D, Jurczak MJ, Rahimi Y, Cline GW, Dufour S, Birkenfeld AL, Rothman DL, Carpenter TO, Insogna K, Petersen KF, Bergwitz C, Shulman GI. Hypophosphatemia promotes lower rates of muscle ATP synthesis. FASEB Journal : Official Publication Of The Federation Of American Societies For Experimental Biology 2016, 30:3378-3387. 2016
Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis.
Dasgupta D, Wee MJ, Reyes M, Li Y, Simm PJ, Sharma A, Schlingmann KP, Janner M, Biggin A, Lazier J, Gessner M, Chrysis D, Tuchman S, Baluarte HJ, Levine MA, Tiosano D, Insogna K, Hanley DA, Carpenter TO, Ichikawa S, Hoppe B, Konrad M, Sävendahl L, Munns CF, Lee H, Jüppner H, Bergwitz C. Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis. Journal Of The American Society Of Nephrology : JASN 2014, 25:2366-75. 2014
Full List of PubMed Publications
- Rose E, Lee D, Xiao E, Zhao W, Wee M, Cohen J, Bergwitz C: Endocrine regulation of MFS2 by branchless controls phosphate excretion and stone formation in Drosophila renal tubules. Sci Rep. 2019 Jun 19; 2019 Jun 19. PMID: 31217461
- Bergwitz C, Miyamoto KI: Hereditary hypophosphatemic rickets with hypercalciuria: pathophysiology, clinical presentation, diagnosis and therapy. Pflugers Arch. 2019 Jan; 2018 Aug 14. PMID: 30109410
- Chande S, Bergwitz C: Role of phosphate sensing in bone and mineral metabolism. Nat Rev Endocrinol. 2018 Nov. PMID: 30218014
- Caballero D, Li Y, Fetene J, Ponsetto J, Chen A, Zhu C, Braddock DT, Bergwitz C: Intraperitoneal pyrophosphate treatment reduces renal calcifications in Npt2a null mice. PLoS One. 2017; 2017 Jul 13. PMID: 28704395
- Li Y, Caballero D, Ponsetto J, Chen A, Zhu C, Guo J, Demay M, Jüppner H, Bergwitz C: Response of Npt2a knockout mice to dietary calcium and phosphorus. PLoS One. 2017; 2017 Apr 27. PMID: 28448530
- Caballero D, Li Y, Ponsetto J, Zhu C, Bergwitz C: Impaired urinary osteopontin excretion in Npt2a-/- mice. Am J Physiol Renal Physiol. 2017 Jan 1; 2016 Oct 26. PMID: 27784695
- Pesta DH, Tsirigotis DN, Befroy DE, Caballero D, Jurczak MJ, Rahimi Y, Cline GW, Dufour S, Birkenfeld AL, Rothman DL, Carpenter TO, Insogna K, Petersen KF, Bergwitz C, Shulman GI: Hypophosphatemia promotes lower rates of muscle ATP synthesis. FASEB J. 2016 Oct; 2016 Jun 23. PMID: 27338702
- Dasgupta D, Wee MJ, Reyes M, Li Y, Simm PJ, Sharma A, Schlingmann KP, Janner M, Biggin A, Lazier J, Gessner M, Chrysis D, Tuchman S, Baluarte HJ, Levine MA, Tiosano D, Insogna K, Hanley DA, Carpenter TO, Ichikawa S, Hoppe B, Konrad M, Sävendahl L, Munns CF, Lee H, Jüppner H, Bergwitz C: Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis. J Am Soc Nephrol. 2014 Oct; 2014 Apr 3. PMID: 24700880
- Page K, Bergwitz C, Jaureguiberry G, Harinarayan CV, Insogna K: A patient with hypophosphatemia, a femoral fracture, and recurrent kidney stones: report of a novel mutation in SLC34A3. Endocr Pract. 2008 Oct. PMID: 18996815