Pseudohypoparathyroidism (PHP) type 1 is an autosomal dominant disorder characterized by biochemical hypoparathyroidism due to resistance of target tissues to parathyroid hormone (PTH). Two fundamentally different forms of PHP type 1 have been described. In PHP type 1a, mutations in the GNAS1 gene lead to reduced expression or activity of the (alpha subunit of the G protein (Gs-alpha) that couples heptahelical receptors for PTH and many other hormones to activation of adenylyl cyclase. Accordingly, widespread deficiency of Gs-alpha is associated with resistance not only to PTH but also to other hormones that act by stimulating adenylyl cyclase. By contrast, Gs-alpha is normal in PHP type 1b, and hormone resistance is limited to PTH target tissues. These observations had suggested that the defect in PHP type 1b was the type 1 PTH receptor, but molecular analysis of this gene has not revealed mutations. The goal of this project is to identify and characterize the gene for PHP type 1b using linkage analysis and a candidate gene approach. The GCRC is used to evaluate the endocrine and metabolic characteristics of patients with PHP type 1 in order to determine whether they have the type 1a or type 1b variant. Subjects who meet the criterion for PHP type 1b will undergo a comprehensive analysis of their family in order to recruit all affected and unaffected relatives. Genomic DNA samples will be obtained from all familial and sporadic cases in order to perform the genetic linkage analyses and to test candidate genes. Once the PHP1b gene is identified, the long-range goal will be to characterize the function of the gene product, to examine genotype-phenotype correlations, and to understand its role in regulating expression or action of the PTH receptor in health and disease.
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