Deficient activity of receptor-cyclase coupling protein is transformed lymphoblasts of patients with pseudohypoparathyroidism, type I.

Erythrocytes of many patients with pseudohypoparathyroidism, type 1 (PHP-I) exhibit quantitatively reduced activity of the N protein, the guanine nucleotide-binding regulatory component of adenylate cyclase. We have designated this group of patients PHP-Ia to distinguish them from PHP-Ib patients, in whom erythrocyte N activity is quantitatively normal. In virus-transformed lymphoblasts of three normal, three PHP-Ia, and two PHP-Ib subjects, we compared N and adenylate cyclase activities, as well as cAMP accumulation and susceptibility to radiolabeling in the presence of [32P]NAD and cholera toxin. In comparison to normal lymphoblasts, N activities were reduced by approximately 50% in lymphoblasts of the PHP-Ia patients, but were not reduced in lymphoblasts from the PHP-Ib patients. Toxin-catalyzed radiolabeling of the 42,000 molecular weight subunit of the N protein was also reduced in lymphoblasts of the PHP-Ia patients. These results are consistent with the hypothesis that N deficiency is generalized in tissues of PHP-Ia patients. Deficient lymphoblast N activity in PHP-Ia was not associated with decreases in adenylate cyclase activity or cAMP accumulation, probably because these activities involve many potential regulable cellular components in addition to the N protein.