HHRH is an autosomal recessive disorder. In a large Bedouin kindred affected by HHRH, we recently described a homozygous frameshift mutation (c.228del) in SLC34A3, the gene encoding NaPi-llc (Am J Hum Genetics, 78:179-192, 2006). Further analysis of this family indicated that several homozygous individuals revealed only hypercalciuria, while bone changes consistent with rickets were absent at the time of investigation. Similarly, some heterozygous individuals showed no evidence for hypercalciuria. Besides the c.228del mutation, several different homozygous or compound heterozygous missense, frameshift and deletion SLC34A3 mutations were found in seven additional HHRH kindreds and in sporadic cases, supporting the conclusion that HHRH is a monogenic disorder. Renal stones were seen in some of these cases. Transient expression of EGFP (enhanced green fluorescence protein)-tagged wild-type and mutant NaPi-llc in Opossum kidney (OK) cells indicated that insertion into the brush border membrane is severely disturbed by the presence of NaPi-llc mutations G196R, R468VV, and delL.527, while other NaPi-llc mutations show normal expression in apical patches. To assess the impact of these fully expressed NaPi-llc mutations on phosphate uptake, we established a Xenopus oocyte mRNA injection model (Aim 1a).
Aim 1 b will expand these in vitro studies to determine relative importance of NaPi-llc compared to NaPi-lla in mammalian phosphate homeostasis. Furthermore, a targeting vector was constructed to ablate the gene encoding Npt-2c, the murine ortholog of NaPi-llc. Heterozygous animals are expected to develop only idiopathic hypercalciuria, while the homozygous ablation of Npt-2c is predicted to lead to HHRH, despite the presence of Npt-2a (Aim 2). Because of this apparent variability in phenotype of individuals who are either heterozygous and homozygous for mutations in SLC34A3, it will be important to determine which factors contribute to the expressivity of this mutation in the Bedouin kindred (Aim 3). Abnormal renal calcium and phosphate handling is seen in patients with nephrocalcinosis, nephrolithiasis and chronic kidney disease (CKD), disorders that affect a large number of Americans today. A K08 career development award by the NIH will help me to further explore the importance of NaPi-llc in mammalian biology, and allow me to acquire new skills on my way to becoming an independent scientist.
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|Caballero, Daniel; Li, Yuwen; Fetene, Jonathan et al. (2017) Intraperitoneal pyrophosphate treatment reduces renal calcifications in Npt2a null mice. PLoS One 12:e0180098|
|Dasgupta, Debayan; Wee, Mark J; Reyes, Monica et al. (2014) Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis. J Am Soc Nephrol 25:2366-75|
|Bergwitz, Clemens; Rasmussen, Matthew D; DeRobertis, Charles et al. (2012) Roles of major facilitator superfamily transporters in phosphate response in Drosophila. PLoS One 7:e31730|
|Bergwitz, Clemens; Jüppner, Harald (2012) FGF23 and syndromes of abnormal renal phosphate handling. Adv Exp Med Biol 728:41-64|
|Bergwitz, Clemens (2012) Dietary phosphate modifies lifespan in Drosophila. Nephrol Dial Transplant 27:3399-406|
|Yu, Y; Sanderson, S R; Reyes, M et al. (2012) Novel NaPi-IIc mutations causing HHRH and idiopathic hypercalciuria in several unrelated families: long-term follow-up in one kindred. Bone 50:1100-6|
|Phulwani, Priya; Bergwitz, Clemens; Jaureguiberry, Graciana et al. (2011) Hereditary hypophosphatemic rickets with hypercalciuria and nephrolithiasis-identification of a novel SLC34A3/NaPi-IIc mutation. Am J Med Genet A 155A:626-33|
|Bergwitz, Clemens; Juppner, Harald (2011) Phosphate sensing. Adv Chronic Kidney Dis 18:132-44|
|Bergwitz, Clemens; Collins, Michael T; Kamath, Ravi S et al. (2011) Case records of the Massachusetts General Hospital. Case 33-2011. A 56-year-old man with hypophosphatemia. N Engl J Med 365:1625-35|
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