X-linked hypophosphatemia (XLH), the most prevalent form of inherited rickets in humans, is caused by mutations in the PHEX gene, which encodes a protein with high homology to the M13 family of type-II integral membrane zinc metallopeptidases. We created an online mutation database, PHEXdb (http://data.mch.mcgill.ca/phexdb), to catalogue PHEX mutations identified in XLH patients, and found that missense mutations account for 22% of the 157 mutations reported to date. We also undertook to examine the effects of eight missense mutations (C85R, D237G, Y317F, G579R, G579V, S711R, A720T, and F731Y) on synthesis, glycosylation, cellular trafficking, and catalytic activity of the recombinant proteins using several approaches. The wild-type protein was resistant to endoglycosidase H (endo H), indicating that it is fully glycosylated. In addition, biotinylation and immunofluorescence studies revealed that the wild-type protein resides at the cell surface. The D237G, Y317F and F731Y mutant PHEX proteins were also endo H resistant and thus terminally glycosylated. In contrast, endo H digestion demonstrated that C85R, G579R, G579V, S711R and A720T were not terminally glycosylated. Furthermore, immunofluorescence showed that C85R, G579R and S711R were sequestered in the endoplasmic reticulum (ER). A secreted form of wild-type and mutant PHEX (secPHEX) proteins was generated to examine catalytic activity, using a synthetic fluorogenic peptide substrate. For this purpose, rescue of ER-trapped mutant proteins was attempted by growing transfected cells at 26°C. Low temperature was able to rescue three of the five trapped mutant proteins (G579V, S711R and A720T). Residual catalytic activity was observed with four mutant proteins (D237G, Y317F, A720T and F731Y) relative to the wild-type. However, the rescued S711R mutant was devoid of catalytic activity. Finally, limited proteolysis with trypsin and endoproteinase Glu-c revealed that the mutations D237G and F731Y induce conform

This study shows that mice homozygous for the disrupted renal sodium-phosphate (Na+-Pi) cotransporter, Npt2, (Npt2 KO) failed to show an age-dependent decrease in renal Na+-Pi cotransport or an adaptive increase in renal Na+-Pi cotransport in response to dietary Pi restriction. None of the other known renal Na+ -Pi cotransporters could compensate for the loss of Npt2. Additionally, Npt2 gene ablation resulted in a marked decrease in osteoclast number that persisted with age. Although mineral apposition rate was normal at 25- and 115-days of age in Npt2 KO mice, bone formation rate was increased at 115-days of age. These data demonstrate that Npt2 gene expression is necessary for an age-dependent decrease in renal Na+-Pi cotransport and for the renal adaptive response to dietary Pi deprivation, and that Npt2 expression is essential for normal osteoclast function and influences bone formation.

No description available.

No description available.

No description available.

No description available.

X-linked hypophosphataemia (XLH) is the most common form of inherited rickets that leads to deformities in the lower limbs, poor tooth and skeletal mineralization, and disproportionate short stature in children. In adults, it is often complicated by enthesopathy, an abnormal mineralization of the tendon-bone attachment. Enthesopathy causes pain and stiffness in affected joints, particularly in the knee, hip, and ankle joints. Enthesopathy is reported as one of the most debilitating symptoms in XLH patients. Previous studies showed that entheses from mice with XLH (Hyp) are characterized by enhanced Bone morphogenic protein (BMP) and Indian hedgehog (IHH) signaling. This study aims to investigate the role of GDF5 in the development of enthesopathy in the Hyp mice. The study has two specific aims: (1) to determine if deleting GDF5 in enthesis (scleraxis-expressing (Scx+)) cells affects BMP/IHH signaling in entheses and (2) to determine if deleting GDF5 in Scx+ cells of Hyp mice attenuates XLH enthesopathy. The study hopes to gain a better understanding of role of GDF5 in enthesis maturation and XLH enthesopathy development. This study finds that deleting GDF5 in wild-type mice does not change normal enthesis maturation. However, deleting GDF5 in Hyp mice attenuates enthesopathy as indicated by decreased BMP/IHH signaling in Hyp entheses. / 2026-03-19T00:00:00Z

Epidermal nevus syndromes encompass a highly heterogeneous group of systemic disorders, characterized by epidermal nevi, and a spectrum of neuromuscular, ocular, and bone abnormalities. Cutaneous-skeletal hypophosphatemia syndrome (CSHS) constitutes a specific sub-entity in which elevated levels of fibroblast growth factor-23 cause hypophosphatemic rickets that are, to date, not amenable to causal therapy. Here, we report the first long-term follow-up of causal treatment with burosumab in a 3-year-old female patient with CSHS. 4 weeks after initiation of burosumab treatment, serum phosphate normalized to age-appropriate levels. Furthermore, long-term follow-up of 42 months revealed significant improvement of linear growth and gross physical functions, including respiratory insufficiency. Radiographic rickets severity as well as subjective bone pain were strongly reduced, and no side effects were observed over the course of treatment. In summary, we, here, report about a successful treatment of hypophosphatemic rickets in CSHS with burosumab over the time course of 42 months. In our patient, burosumab showed convincing efficacy and safety profile, without any loss of effect or increase of dose.

Recognising that NPT2 is the major Na/Pi cotransporter in the kidney, that hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is caused by a renal Pi leak and, that Npt2 knockout mice demonstrate a biochemical phenotype similar to that of patients with HHRH, we sought to determine whether NPT2 was a candidate gene for this disorder. Using single-strand conformation polymorphsim (SSCP) analysis and sequencing in six unrelated pedigrees with the disease, we found no disease-causing mutations. Two polymorphisms were identified in the gene and used as markers to examine segregation of NPT2 with the disease. HHRH did not segregate with the gene markers. In addition, the impact of NPT2 on bone mineral density (BMD) was examined by genotyping a population of 104 individuals for which BMD data was available, and determining whether there was an association between NPT2 genotype and bone density. No significant association was found between NPT2 genotype and BMD.

Thesis advisor: Susan Kelly-Weeder / Refeeding Hypophosphatemia (RH) is the most common complication of nutritional restoration during medical hospitalization for individuals with anorexia nervosa (AN). Characterized by a drop in serum phosphorus levels, consequences of RH can be seen throughout the body and are potentially life threatening. Despite the seriousness of this outcome, little is known about which individuals with AN are at greatest risk of developing RH and best practices for prevention. The purpose of this retrospective cohort study was to examine demographic, feeding, and biochemical factors found in hospitalized adolescent and young adults (AYA) diagnosed with AN that may contribute to the development of RH. Individuals diagnosed with AN who were admitted to Boston Children’s Hospital between the years of 2010-2016 were considered for inclusion. Three hundred charts were analyzed using logistic regression to determine factors associated with RH and multivariate regression to determine factors associated with serum phosphorus nadir. In the final logistic regression model, receiving nasogastric tube feeding (p=0.54), age at admission (p=.022), weight gain during hospitalization (p=.003), serum potassium level (p=.001), and serum magnesium level (p=.024) significantly contributed to the model. Odds of RH were 3 times higher in those who received NG feeding, 1.2 times higher for each year of increasing age, 1.5 times higher for each kilogram of weight gain, 9.2 times higher for each unit reduction in potassium, and 13.7 times higher for each unit reduction in magnesium. With regards to phosphorus nadir, 1-unit increase in magnesium resulted in 1.2 increase in phosphorus, and each unit of admit BMI increased phosphorus by .060. The results indicate that NG feeding, age, weight gain, electrolyte abnormalities, and admit BMI are potential indicators of development of RH in AYA hospitalized with AN. This study will inform clinicians of risk factors associated with RH, and may guide further investigation into the clinical management of AYA diagnosed with AN. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Connell School of Nursing. / Discipline: Nursing.