PTH/PTHRP RECEPTOR DEFECTS IN PSEUDOHYPOPARATHYROIDISM

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Pseudohypoparathyroidism (PHP) is a group of disorders all of which are characterized by PTH resistance; patients manifest hypocalcemia, hyperphosphatemia, and elevated PTH levels. Defining these patients' deficiencies at the molecular level has provided enormous insights into mechanisms by which PTH acts. Patients with PHP Ia have diminished activation of their receptor-adenylate cyclase (AC) effector system by PTH and other hormones, and developmental/skeletal defects (Albright's Hereditary Osteodystrophy (AHO)). Commonly, these patients have deficient or defective G-alpha-s-subunits, although this is not universal. Hormonal resistance probably is explained by the abnormal G-alpha-s, but the link between this biochemical lesion and AHO is unclear. Patients with pseudo-PHP have no hormonal resistance, although they have AHO and G-alpha-s defects, and often are in the same family with PHP Ia patients. An additional defect has been postulated because the G-alpha-s defects appear insufficient to account for all the clinical manifestations. PHP Ib patients have isolated PTH resistance, with normal physical appearance and no G-alpha-s abnormality; these patients most likely have receptor defects, although they too are a heterogeneous population. We have recently cloned cDNA and the gene encoding a human receptor that binds both PTH and PTHrP. When this receptor is activated by either amino-terminal analogs of PTH or PTHrP, it signals through at least two effectors, AC and phospholipase C. We propose to determine the structural and functional properties of PTH/PTHrP receptor(s) and their gene(s) that contribute to disease in these patients. We first will complete characterization of the properties of the normal receptor and its gene (Aim 1). We then will use several approaches to determine the receptor mRNA/gene defects in PHP, initially focusing on PHP Ib (Aim 2). Once mutant receptors are identified, we will characterize their biological properties in multiple bioassays (Aim 3). Determining receptor defects in these patients will not only help to understand the pathophysiology of these related diseases, but will provide insight into the mechanisms of action of PTH and PTHrP. This knowledge, particularly of the role of the PTH/PTHrP receptor system in the skeleton, may lead to more rational intervention in bone diseases, including bone-loss states.