Hiroshi Saito1, Hiroshi Noda1, Philippe Gatault2, Detlef Bockenhauer3,4, Kah Yin Loke5, Olaf Hiort6, Caroline Silve7,8, Erin Sharwood9, Regina Matsunaga Martin10,11, Michael J Dillon3,4, David Gillis12, Mark Harris9,13, Sudhaker D Rao14, Richard M Pauli15, Thomas J Gardella1, Harald Jüppner1,16. 1. Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 2. Service de Néphrologie-Hypertensiologie, Transplantation - Dialyses, University Hospital, Tours, France. 3. University College London Centre for Nephrology, Royal Free Hospital, London, United Kingdom. 4. Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, London, United Kingdom. 5. Department of Pediatrics, National University Hospital, Singapore, Singapore. 6. Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Lübeck, Lübeck, Germany. 7. Service de Biochimie et Génétique Moléculaires, Hôpital Cochin, AP-HP, Paris, France. 8. Centre de Référence des Maladies rares du Calcium et du Phosphore and Filière de Santé Maladies Rares OSCAR, AP-HP, Paris, France. 9. Endocrinology Department, Lady Cilento Children's Hospital, Brisbane, Queensland, Australia. 10. Osteometabolic Disorders Unit, Division of Endocrinology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil. 11. Laboratory of Hormones and Molecular Genetics/LIM42, Division of Endocrinology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil. 12. Department of Pediatrics, Hadassah Hebrew University Hospital, Jerusalem, Israel. 13. Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia. 14. Bone and Mineral Research Laboratory and Division of Endocrinology, Diabetes, and Bone & Mineral Disorders, Department of Medicine, Henry Ford Hospital, Detroit, Michigan. 15. Division of Genetics and Metabolism, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. 16. Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Abstract
Context: Five different activating PTH/PTH-related peptide (PTHrP) receptor (PTHR1) mutations have been reported as causes of Jansen metaphyseal chondrodysplasia (JMC), a rare disorder characterized by severe growth plate abnormalities and PTH-independent hypercalcemia. Objectives: Assess the natural history of clinical and laboratory findings in 24 patients with JMC and characterize the disease-causing mutant receptors in vitro. Patients and Methods: The H223R mutation occurred in 18 patients. T410P, I458R and I458K each occurred in single cases; T410R was present in a father and his two sons. Laboratory records were analyzed individually and in aggregate. Results: Postnatal calcium levels were normal in most patients, but elevated between 0.15 and 10 years (11.8 ± 1.37 mg/dL) and tended to normalize in adults (10.0 ± 1.03 mg/dL). Mean phosphate levels were at the lower end of the age-specific normal ranges. Urinary calcium/creatinine (mg/mg) were consistently elevated (children, 0.80 ± 0.40; adults, 0.28 ± 0.19). Adult heights were well below the 3rd percentile for all patients, except for those with the T410R mutation. Most patients with JMC had undergone orthopedic surgical procedures, most had nephrocalcinosis, and two had advanced chronic kidney disease. The five PTHR1 mutants showed varying degrees of constitutive and PTH-stimulated cAMP signaling activity when expressed in HEK293 reporter cells. The inverse agonist [L11,dW12,W23,Y36]PTHrP(7-36) reduced basal cAMP signaling for each PTHR1 mutant. Conclusions: Except for T410R, the other PTHR1 mutations were associated with indistinguishable mineral ion abnormalities and cause similarly severe growth impairment. Hypercalciuria persisted into adulthood. An inverse agonist ligand effectively reduced in vitro PTH-independent cAMP formation at all five PTHR1 mutants, suggesting a potential path toward therapy.
Context: Five different activating PTH/PTH-related peptide (PTHrP) receptor (PTHR1) mutations have been reported as causes of Jansen metaphyseal chondrodysplasia (JMC), a rare disorder characterized by severe growth plate abnormalities and PTH-independent hypercalcemia. Objectives: Assess the natural history of clinical and laboratory findings in 24 patients with JMC and characterize the disease-causing mutant receptors in vitro. Patients and Methods: The H223R mutation occurred in 18 patients. T410P, I458R and I458K each occurred in single cases; T410R was present in a father and his two sons. Laboratory records were analyzed individually and in aggregate. Results: Postnatal calcium levels were normal in most patients, but elevated between 0.15 and 10 years (11.8 ± 1.37 mg/dL) and tended to normalize in adults (10.0 ± 1.03 mg/dL). Mean phosphate levels were at the lower end of the age-specific normal ranges. Urinary calcium/creatinine (mg/mg) were consistently elevated (children, 0.80 ± 0.40; adults, 0.28 ± 0.19). Adult heights were well below the 3rd percentile for all patients, except for those with the T410R mutation. Most patients with JMC had undergone orthopedic surgical procedures, most had nephrocalcinosis, and two had advanced chronic kidney disease. The five PTHR1 mutants showed varying degrees of constitutive and PTH-stimulated cAMP signaling activity when expressed in HEK293 reporter cells. The inverse agonist [L11,dW12,W23,Y36]PTHrP(7-36) reduced basal cAMP signaling for each PTHR1 mutant. Conclusions: Except for T410R, the other PTHR1 mutations were associated with indistinguishable mineral ion abnormalities and cause similarly severe growth impairment. Hypercalciuria persisted into adulthood. An inverse agonist ligand effectively reduced in vitro PTH-independent cAMP formation at all five PTHR1 mutants, suggesting a potential path toward therapy.
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