The term pseudohypoparathyroidism (PHP) is used for three distinct disorders, PHP type Ia (PHP-Ia), pseudo-PHP (pPHP), and PHP type Ib (PHP-Ib). PHP-Ia is characterized by PTH-resistant hypocalcemia and hyperphosphatemia, impaired function of several other endocrine systems, and a variety of developmental/skeletal defects (Albright's hereditary osteodystrophy (AHO)), including short stature, obesity, impaired intelligence, and skeletal abnormalities. Patients with pPHP are also affected by AHO, but show no resistance toward PTH or other hormones. PHP-Ia and pPHP occur within the same family, and individuals affected by either form show, as a result of inactivating mutations, reduced activity of the stimulatory G protein (Gsa); the Gsa gene is located on chromosome 20q13.3. Recent findings provided strong evidence for paternal imprinting in PHP-Ia/pPHP (i.e. patients with AHO), and showed that the abnormal control of calcium homeostasis, occurs only if the disease is inherited from an obligate female carrier. PHP-Ib patients show only resistance toward PTH, but no AHO phenotype. Since PTH-resistance is the only discernible abnormality in PHP-Ib, the disorder was first thought to be caused by inactivating PTH/PTHrP receptor mutations, but these were excluded by us and others. To continue our search for the molecular defect in PHP-Ib without prior knowledge of its primary structure, we collected several large PHP-Ib kindreds, conducted a genome-wide search with greater than 350 polymorphic microsatellite markers, and obtained linkage with a maximal combined LOD score of 6.48 to chromosome 20q13.3 (the Gsa gene is in same region). Furthermore, we showed that PHP-Ib is paternally imprinted, as is PHP-Ia/pPHP. We now propose to further reduce the linked interval and to confirm the 20q13.3 locus with additional PHP-Ib kindreds (Aim 1), to determine whether Gsa mutations cause the disease, and, if this candidate gene can be excluded, to search for the PHP-Ib gene (Aim 2), to explore the role of the PHP-Ib gene with regard to PTH/PTHrP receptor function (Aim 3), and to explore the importance of the stimulatory G protein in endochondral bone formation using heterozygous Gsa gene ablated mice (Aim 4).
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