Albright's hereditary osteodystrophy (AHO) is an autosomal dominant disorder characterized by an unusual phenotypic appearance and reduced biological activity of the α-subunit of the stimulatory G-protein of adenylyl cyclase (Gsα). In most AHO patients deficient Gsα activity is associated with generalized target organ resistance to hormones that act via stimulation of adenylyl cyclase. This form of the disorder is termed pseudohypoparathyroidism type Ia (PHP Ia). By contrast, other patients with Gsα deficiency fail to demonstrate clinical evidence of hormone resistance and are considered to have the related disorder pseudopseudohypoparathyroidism (pseudoPHP). Previous studies demonstrating deficient Gsα bioactivity in cell membranes from patients with AHO used functional assays that were unable to distinguish between reduced amounts of normal Gsα protein and normal amounts of defective Gsα protein. In the present study we used specific Gsα antisera to analyze immunoactive Gsα protein in erythrocyte and fibroblast membranes from 20 patients with AHO who had either normal or reduced levels of Gsα mRNA. Cell membranes were subjected to immunoblot analysis using Gsα antisera developed against synthetic peptides corresponding to amino acid sequences in the amino- or carboxyl-terminus of the Gsα molecule. Fibroblast membranes from patients with AHO who had reduced or normal levels of Gsα mRNA contained both the 45-and 52-kDa forms of the Gsα protein in quantities that were significantly less [mean ± SE, 52 ± 6%; (n = 8) for reduced mRNA and 35 ± 19% (n = 2) for normal mRNA, percentage of control values] than those present in membranes from normal subjects. Similar reductions were found in the level of the 45-kDa form of Gsα in erythrocyte membranes from all AHO patients studied [40 ± 4% (mean ± SE) of control values]. No abnormal forms of Gsα protein were detected. Cell membranes from patients with PHP type Ia and from patients with pseudoPHP contained levels of immunoactive Gsα that were equivalently reduced (43 ± 4% vs. 42 ± 5%, respectively). By contrast, erythrocyte membranes from patients with PHP type Ib, who have normal Gsα activity, had normal levels of Gsα immunoactivity (101 ± 7%). These results indicate that most patients with AHO have reduced levels of Gsα protein as the basis for deficient Gsα bioactivity.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of Clinical Endocrinology and Metabolism|
|State||Published - Nov 1990|
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism