Projects

A recent survey of all known kindreds with hereditary hypophosphatemic rickets with hypercalciuria (HHRH) identified a number of unmet therapeutic needs for individuals with this rare disorder (Dasgupta et al. 2014). For example, while the rachitic bone disease of HHRH responds well to oral phosphate supplementation, it is completely unknown whether adult height is affected and if enthesopathies can develop as they do in X-linked hypophosphatemia (XLH). It is also not clear if the renal phosphate-leak persists throughout life, whether therapy can be stopped just as is done in cases of autosomal dominant hypophosphatemic rickets (ADHR), and if HHRH predisposes individuals to accelerated bone loss during adulthood. In addition, no biomarkers exist for the myopathy often seen in individuals with severe hypophosphatemia, and renal calcifications observed with HHRH often delay therapy with oral phosphate supplements because, despite the benefit of improved hypercalciuria with therapy, the resulting phosphaturia may worsen this complication of HHRH. Given the clear need to carefully characterize HHRH, we are currently establishing disease progression, symptoms, biochemical and imaging biomarkers for HHRH, and adverse event information of standard therapies for HHRH. The lab’s long-term goal is to conduct trials for innovative therapies of hypophosphatemic rickets, osteomalacia and myopathy.

Recent Publications

Bergwitz C, Miyamoto K Hereditary Hypophosphatemic Rickets with Hypercalciuria Pathophysiology, Clinical Presentation, Diagnosis and Therapy, Pflugers Arch. 2018 Aug 14. doi: 10.1007/s00424-018-2184-2. [Epub ahead of print] Review. PMID: 30109410R12. https://link.springer.com/epdf/10.1007/s00424-018-2184-2?author_access_token=h2h9P2y5NL8n8zAdcnd4l_e4RwlQNchNByi7wbcMAY4Ec290Ob1JTvjMyJZdzqsSL850K4oZZPy35ipi_Jgp3stpWeCCDDp_7rEd6TG-UrEGQZuX230duBTUXAdnL5MN6HFB0MRGUzTc9l3tKeVLBA%3D%3D

Dasgupta D, Wee MJ, Reyes M, Li Y, Simm PJ, Sharma A, Schlingmann K-P, 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 S, Konrad M, Sävendahl L, Munns CF, Lee H, Jüppner H and Bergwitz C Mutations in SLC34A3/NPT2c Are Associated with Kidney Stones and Nephrocalcinosis. JASN April 3, 2014, doi: 10.1681/ASN.201310108

Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, Frappier D, Burkett K, Carpenter TO, Anderson D, Garabedian M, Sermet I, Fujiwara TM, Morgan K, Tenenhouse HS, Jüppner H. SLC34A3 Mutations in Patients with Hereditary Hypophosphatemic Rickets with Hypercalciuria Predict a Key Role for the Sodium-Phosphate Cotransporter NaPi- IIc in Maintaining Phosphate Homeostasis. Am J Hum Genet. 2006;78(2):179-92.

We are currently using fruit flies (Bergwitz et al. 2012 and 2013) and mouse models (Beck et al. 1998) with genetically modified phosphate transporters to study the metabolic and endocrine effects of phosphate that promote the formation of renal calcifications, an important complication of oral phosphate therapy used to treat hypophosphatemic rickets.

We are also interested in understanding how phosphate influences lifespan. Building on the observation that dietary phosphate reduces the longevity of flies (Bergwitz et al. 2013), we are using cell-based and in vivo assays to determine how phosphate affects longevity, with the ultimate goal of identifying conserved intracellular pathways by which phosphate regulates longevity in higher species and humans.

Recent 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. Scientific Reports 2019 Sci Rep. 2019 Jun 19;9(1):8798

Bergwitz C, Wee MJ, Sinha S, Huang J, DeRobertis C, Mensah LB, Cohen J, Friedman A, Kulkarni M, Hu Y, Vinayagam A, Schnall-Levin M, Berger B, Perkins LA, Mohr SE, Perrimon N 2013 Genetic determinants of phosphate response in Drosophila. PLoS ONE 8(3): e56753. doi:10.1371/journal.pone.0056753

Bergwitz C, Rasmussen MD, Derobertis C, Wee MJ, Sinha S, Chen HH, Huang J, and Perrimon N. Roles of major facilitator superfamily transporters in phosphate response in Drosophila. PLoS One 7: e31730, 2012.

The lab is interested in understanding how human and other metazoan cells sense inorganic phosphate. We performed a genome-wide RNAi screen (Bergwitz et al. 2013) to identify genes important for phosphate sensing inside cells, and are currently developing approaches to understand the flow of information along these genes. Along with additional genome-wide screens to identify metabolic and endocrine sensors for phosphate, these studies will add to our knowledge of the signaling pathways by which phosphate affects cell metabolism and endocrine functions.

Recent Publications

Chande S, Bergwitz C, Role of phosphate sensing in bone and mineral metabolism Nat Rev Endocrinol. 2018 Sep 14. doi: 10.1038/s41574-018-0076-3. [Epub ahead of print] Review. PMID: 30218014

Bergwitz C, Wee MJ, Sinha S, Huang J, DeRobertis C, Mensah LB, Cohen J, Friedman A, Kulkarni M, Hu Y, Vinayagam A, Schnall-Levin M, Berger B, Perkins LA, Mohr SE, Perrimon N 2013 Genetic determinants of phosphate response in Drosophila. PLoS ONE 8(3): e56753. doi:10.1371/journal.pone.0056753