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A Form of Jansen’s Metaphyseal Chondrodysplasia with Limited Metabolic and Skeletal Abnormalities Is Caused by a Novel Activating Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Mutation

Endocrine Unit (M.B., H.J.) and Department of Medicine and Pediatric Nephrology Unit (H.J.), Massachussets General Hospital for Children, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Departments of Human Genetics (A.R.-R.), Nephrology (J.S.), and Pediatrics (D.G.), Hadassah Hebrew University Hospital, Jerusalem, Israel 91120; Department of Pediatric Nephrology (I.W.), Western Galilee Hospital, Naharyia, Israel 22100; and Department of Pediatric Orthopedics (S.W.), Dana Children’s Hospital, Tel Aviv Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 64239

Address all correspondence and requests for reprints to: Harald Jüppner, Endocrine Unit, Massachusetts General Hospital, Wellman 5, Boston, Massachusetts 02114. E-mail: jueppner{at}helix.mgh.harvard.edu.

A novel heterozygous PTH/PTHrP receptor missense mutation (T410R) was identified in a male and his two sons who are all affected by a less severe form of Jansen’s metaphyseal chondrodysplasia (JMC). JMC is a rare disorder that is typically characterized by severe growth plate abnormalities that lead to short-limbed dwarfism. Furthermore, affected individuals usually show significant hypercalcemia, despite normal or undetectable levels of PTH and PTHrP. In contrast, the three affected members of this new family showed only mild skeletal dysplasia, comparatively normal stature, and blood calcium concentrations either within or at the upper end of the normal range. However, PTH levels were suppressed, and urinary calcium excretion was elevated, which led to nephrolithiasis in both children. When expressed in COS-7 cells, the PTH/PTHrP receptor with the T410R mutation led to agonist-independent cAMP formation, which was less pronounced than that observed with the previously identified T410P mutant. Our findings indicate that a mild form of JMC has been identified that is characterized by less pronounced skeletal and laboratory abnormalities.

This work was supported in part by grants from the National Institutes of Health (DK-50708 to H.J. and DK062973 to M.B.).

M.B. and A.R.-R. contributed equally to this work.

Abbreviations: CG, Chorionic gonadotropin; JMC, Jansen’s metaphyseal chondrodysplasia.

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