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New form of pseudohypoparathyroidism with abnormal catalytic adenylate cyclase
D Barrett1, N A Breslau, M B Wax
1Division of Endocrinology and Metabolism, Medical College of Virginia, Richmond 23298.
Abstract:
Patients with pseudohypoparathyroidism type Ia have resistance to multiple hormones because of deficient activity of the stimulatory guanine nucleotide-binding protein (Gs) 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 Gs activity, the biochemical abnormality responsible for hormone resistance 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 Gs after fluoride ion treatment produced only 52% of normal activity, yet fibroblast membrane Gs activity measured by cyc- complementation was normal. Activation of the catalytic unit of adenylate cyclase with manganese produced 49% of normal activity; manganese plus forskolin produced 54% of normal adenylate cyclase activity. beta-Adrenergic receptor coupling to Gs 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.
Insights
Pseudohypoparathyroidism can stem from a defective adenylate cyclase catalytic unit, not just Gs protein issues. This finding explains hormone resistance in patients with normal Gs activity.
Area of Science:
- Endocrinology
- Molecular Biology
- Biochemistry
Background:
- Pseudohypoparathyroidism type Ia involves hormone resistance due to deficient Gs protein activity.
- A subset of patients exhibits hormone resistance despite normal erythrocyte Gs activity, with an undefined biochemical cause.
Purpose of the Study:
- To investigate the biochemical basis of hormone resistance in a patient with pseudohypoparathyroidism and normal Gs activity.
- To determine if a defect in the adenylate cyclase catalytic unit contributes to hormone resistance.
Main Methods:
- Cultured skin fibroblasts from the patient were used.
- Adenylate cyclase activity was measured after stimulation with fluoride ions, manganese, and forskolin.
- Gs activity was assessed using cyc-complementation; beta-adrenergic receptor coupling and phosphodiesterase activity were also evaluated.
Main Results:
- Fibroblast membranes showed reduced adenylate cyclase stimulation (52% of normal) with fluoride ions.
- Gs activity measured by cyc-complementation was normal.
- Activation of the catalytic unit with manganese yielded 49% of normal activity, and with manganese plus forskolin, 54%.
Conclusions:
- A defect in the catalytic unit of adenylate cyclase is proposed as the cause of hormone resistance in this patient.
- This defect may represent a mechanism for clinical hormone resistance in pseudohypoparathyroidism patients with normal Gs activity.