Gs is the ubiquitously expressed
heterotrimeric G protein that couples receptors to the effector
enzyme adenylyl cyclase and is required for receptor-stimulated intracellular cAMP generation. Activated receptors promote the exchange of
GTP for
GDP on the Gs alpha-subunit (Gs(alpha)), resulting in Gs activation; an intrinsic
GTPase activity of Gs(alpha) deactivates Gs by hydrolyzing bound
GTP to
GDP. Mutations of Gs(alpha) residues involved in the
GTPase reaction that lead to constitutive activation are present in endocrine
tumors,
fibrous dysplasia of bone, and
McCune-Albright syndrome. Heterozygous loss-of-function mutations lead to
Albright hereditary osteodystrophy (AHO), a disease characterized by short stature,
obesity, and skeletal defects, and are sometimes associated with
progressive osseous heteroplasia. Maternal transmission of Gs(alpha) mutations leads to AHO plus resistance to several
hormones (e.g.,
parathyroid hormone) that activate Gs in their target tissues (
pseudohypoparathyroidism type IA), while paternal transmission leads only to the AHO phenotype (
pseudopseudohypoparathyroidism). Studies in both mice and humans demonstrate that Gs(alpha) is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues and biallelically expressed in most other tissues. This likely explains why multihormone resistance occurs only when Gs(alpha) mutations are inherited maternally. The Gs(alpha) gene GNAS1 has at least four alternative promoters and first exons, leading to the production of alternative gene products including Gs(alpha), XL alphas (a novel Gs(alpha)
isoform expressed only from the paternal allele), and NESP55 (a
chromogranin-like
protein expressed only from the maternal allele). The fourth alternative promoter and first exon (exon 1A) located just upstream of the Gs(alpha) promoter is normally methylated on the maternal allele and is transcriptionally active on the paternal allele. In patients with
parathyroid hormone resistance but without AHO (
pseudohypoparathyroidism type IB), the exon 1A promoter region is unmethylated and transcriptionally active on both alleles. This GNAS1 imprinting defect is predicted to decrease Gs(alpha) expression in tissues where Gs(alpha) is normally imprinted and therefore to lead to renal
parathyroid hormone resistance.