A disruptive mutation in Exon 3 of the GNAS gene with Albright hereditary osteodystrophy, normocalcemic pseudohypoparathyroidism, and selective long transcript variant Gsα-L deficiency

Objective: The GNAS gene encodes the alpha-subunit of stimulatory G proteins, which play a crucial role in intracellular signal transduction of peptide and neurotransmitter receptors. In addition to transcript variants that differ in their first exon due to different promoters, there are two long ( Gs alpha-L) and two short ( Gs alpha-S) splice variants, created by alternative splicing. Heterozygous inactivating maternally inherited mutations of GNAS lead to a phenotype in which Albright hereditary osteodystrophy is associated with pseudohypoparathyroidism type Ia. Methods and Results: The GNAS gene of a 10-yr-old girl with brachymetacarpia, mental retardation, normocalcemic pseudohypoparathyroidism, and hypothyroidism was investigated. We found a heterozygous insertion of an adenosine in exon 3 altering codon 85 and leading to a frame shift inducing a stop codon in exon 4. Molecular studies of cDNA from blood RNA demonstrated normal, biallelic expression of Gs alpha-S transcripts, whereas expression of Gs alpha-L transcripts from the maternal allele was reduced. Immunoblot analysis revealed a reduced Gs alpha-L protein level to about 50%, whereas the protein level of Gs alpha-S was unaltered. Furthermore, the Gs alpha protein activity in erythrocyte membranes was diminished to about 75% of normal. Both the reduced activity and the mutation were also found in the mother and the affected younger brother. Conclusion: This report demonstrates the first evidence for a pathogenic mutation in exon 3 of the GNAS gene. The mutation is associated with a phenotype of Albright hereditary osteodystrophy and pseudohypoparathyroidism type Ia due to selective deficiency of Gs alpha-L and a partial reduction of Gs alpha activity.