New form of pseudohypoparathyroidism with abnormal catalytic adenylate cyclase

Patients with pseudohypoparathyroidism type Ia have resistance to multiple hormones because of deficient activity of the stimulatory guanine nucleotide-binding protein (G(s)) that couples membrane receptors to activation of adenylate cyclase. However, in a subset of patients with pseudohypoparathyroidism who have resistance to multiple hormones yet possess normal erythrocyte membrane G(s) activity, the biochemical abnormality responsible for hormone resitance has remained undefined. Cultured skin fibroblasts were derived from a patient with this atypical form of pseudohypoparathyroidism. In the patient's fibroblast membranes, adenylate cyclase stimulation mediated by G(s) after fluoride ion treatment produced only 52% of normal activity, yet fibroblast membrane G(s) activity measured by cyc^- complementation was normal. Activation of the catalytic unit of adenylate cyclase with manganese produced 49% of the normal activity; manganese plus forskolin produced 54% of normal adenylate cyclase activity. β-Adrenergic receptor coupling to G(s) and phosphodiesterase activity were normal. A defect in the catalytic unit of adenylate cyclase can account for these results and may be a mechanism for clinical resistance to multiple hormones that act through adenylate cyclase.