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Keywords:

  • G proteins;
  • cAMP;
  • Albright hereditary osteodystrophy;
  • McCune-Albright syndrome;
  • fibrous dysplasia;
  • progressive osseous heteroplasia;
  • genomic imprinting

Abstract: 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 α-subunit (Gsα), resulting in Gs activation; an intrinsic GTPase activity of Gsα deactivates Gs by hydrolyzing bound GTP to GDP. Mutations of Gsα 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 Gsα 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 Gsα 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 Gsα mutations are inherited maternally. The Gsα gene GNAS1 has at least four alternative promoters and first exons, leading to the production of alternative gene products including Gsα, XLαs (a novel Gsα 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 Gsα 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 Gsα expression in tissues where Gsα is normally imprinted and therefore to lead to renal parathyroid hormone resistance.