Albright's hereditary osteodystrophy is an autosomal dominant disorder characterized by a short stature, brachydactyly, subcutaneous ossifications, and reduced expression or function of the α subunit of the stimulatory G protein (G_sα) of adenylate cyclase, which is necessary for the action of parathyroid and other hormones that use cyclic AMP as an intracellular second messenger.

We identified a unique G_sα protein in erythrocytes from two related patients with Albright's hereditary osteodystrophy and reduced G_sα bioactivity. The G_sα variant was recognized by a carboxyl terminal—specific G_sα antiserum but not by polyclonal antiserums specific for the amino terminus of G_sα. To investigate the molecular basis for this structurally abnormal G_sα protein, we studied the G_sα gene by restriction-endonuclease analysis. DNA from the two patients had an abnormal restriction-fragment pattern when digested with Ncol, which was consistent with loss of an Ncol restriction site in exon 1 of one G_sα allele. Amplification of a 260-base-pair region that includes exon 1 of the G_sα gene and direct sequencing of the amplified DNA revealed an A-to-G-transition at position +1 in one G_sα allele from each of the two patients. This mutation converts the initiator ATG (methionine) codon to GTG (valine), blocking initiation of translation at the normal site. Translation of the abnormal G_sα messenger RNA would result in the synthesis of a truncated G_sa molecule lacking the amino terminus.

We conclude that in at least some patients with Albright's hereditary osteodystrophy, the disease is caused by a single-base substitution in the G_sα gene and is thus due to an inherited mutation in a human G protein. (N Engl J Med 1990; 322:1412–9.)