Determination of Gs alpha protein activity in Albright's hereditary osteodystrophy

Albright's hereditary osteodystrophy (AHO) is a heterogeneous clinical entity in part associated with pseudohypoparathyroidism (PHP) and other endocrinopathies. It may be caused by diminished Gs alpha protein activity. Heterozygous mutations in the underlying GNAS gene on chromosome 20 have been described. One hundred and six patients with suspected AHO, were investigated, of whom 93 showed a laboratory profile of PHP with low or normal calcium and elevated parathormone with normal vitamin D metabolites, and 13 had no endocrine abnormalities. Gs alpha activity was determined in isolated erythrocyte membranes. Molecular genetic analysis of GNAS exons 2-13 was initiated. Significantly reduced Gs alpha activity was found in 91 patients. In 53 patients with reduced Gs alpha activity, a mutation within GNAS was demonstrated. The mutation detection rate was much lower in AHO patients without endocrinopathies than in those who had PHP. In addition, three of the 15 patients with AHO features but normal Gs alpha activity had genetic variations of GNAS. We conclude that determination of Gs alpha activity can be used as a diagnostic screening procedure in patients with suspected AHO. However, the mutation detection rate in GNAS is highly variable. The genetic heterogeneity of AHO needs further investigation.