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Endocrine Manifestations of Stimulatory G Protein -Subunit Mutations and the Role of Genomic Imprinting

Metabolic Diseases Branch (L.S.W., S.Y., J.L.), National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Molecular, Cellular, and Craniofacial Biology (D.R.W.), University of Louisville School of Dentistry, Louisville, Kentucky 40202

Correspondence: Address all correspondence and requests for reprints to: Dr. Lee S. Weinstein, Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda Maryland 20892-1752. E-mail: leew{at}amb.niddk.nih.gov

The heterotrimeric G protein G_s couples hormone receptors (as well as other receptors) to the effector enzyme adenylyl cyclase and is therefore required for hormone-stimulated intracellular cAMP generation. Receptors activate G_s by promoting exchange of GTP for GDP on the G_s -subunit (G_s) while an intrinsic GTPase activity of G_s that hydrolyzes bound GTP to GDP leads to deactivation. Mutations of specific G_s residues (Arg²⁰¹ or Gln²²⁷) that are critical for the GTPase reaction lead to constitutive activation of G_s-coupled signaling pathways, and such somatic mutations are found in endocrine tumors, fibrous dysplasia of bone, and the McCune-Albright syndrome. Conversely, heterozygous loss-of-function mutations may lead to Albright hereditary osteodystrophy (AHO), a disease characterized by short stature, obesity, brachydactyly, sc ossifications, and mental deficits. Similar mutations are also associated with progressive osseous heteroplasia. Interestingly, paternal transmission of GNAS1 mutations leads to the AHO phenotype alone (pseudopseudohypoparathyroidism), while maternal transmission leads to AHO plus resistance to several hormones (e.g., PTH, TSH) that activate G_s in their target tissues (pseudohypoparathyroidism type IA). Studies in G_s knockout mice demonstrate that G_s is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues (e.g., renal proximal tubule, the major site of renal PTH action), while being biallelically expressed in most other tissues. Disrupting mutations in the maternal allele lead to loss of G_s expression in proximal tubules and therefore loss of PTH action in the kidney, while mutations in the paternal allele have little effect on G_s expression or PTH action. G_s has recently been shown to be also imprinted in human pituitary glands. The G_s gene GNAS1 (as well as its murine ortholog Gnas) has at least four alternative promoters and first exons, leading to the production of alternative gene products including G_s, XLs (a novel G_s isoform that is expressed only from the paternal allele), and NESP55 (a chromogranin-like protein that is expressed only from the maternal allele). A fourth alternative promoter and first exon (exon 1A) located approximately 2.5 kb upstream of the G_s promoter is normally methylated on the maternal allele and transcriptionally active on the paternal allele. In patients with isolated renal resistance to PTH (pseudohypoparathyroidism type IB), the exon 1A promoter region has a paternal-specific imprinting pattern on both alleles (unmethylated, transcriptionally active), suggesting that this region is critical for the tissue-specific imprinting of G_s. The GNAS1 imprinting defect in pseudohypoparathyroidism type IB is predicted to decrease G_s expression in renal proximal tubules. Studies in G_s knockout mice also demonstrate that this gene is critical in the regulation of lipid and glucose metabolism.

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