Constitutively Active PTH/PTHrP Receptors Cause Jansen’s Metaphyseal Chondrodysplasia

Endocrine disorders are typically caused by excessive or insufficient production of an otherwise normal hormone. However, in recent years, several endocrine disorders were shown to be caused by other defects, i.e., mutations in peptide hormones, their cognate receptors, G proteins, or downstream effectors (1 ). Although such defects are extremely uncommon and thus provide only a rare diagnostic challenge, their definition at the molecular level often provided important novel insights into the biological significance of the affected protein and/or its functional properties. This is illustrated by the discovery that Jansen’s metaphyseal chondrodysplasia, a rare genetic disorder characterized by short-limbed dwarfism and severe hormone-independent hypercal-cemia, is caused by activating mutations in the parathyroid hormone (PTH) PTH-related peptide (PTHrP) receptor. These findings are likely to have significant implications for understanding the biological importance of the PTH/PTHrP receptor in addition to its role in regulating mineral ion homeostasis.