Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting

The heterotrimeric G protein G(s) couples hormone receptors (as well as oth er receptors) to the effector enzyme adenylyl cyclase and is therefore requ ired for hormone-stimulated intracellular cAMP generation. Receptors activa te G(s) by promoting exchange of GTP for GDP on the G(s) alpha -subunit (G( s)alpha) while an intrinsic GTPase activity of G(s)alpha that hydrolyzes bo und GTP to GDP leads to deactivation. Mutations of specific G(s)alpha resid ues (Arg(201) or Gln(227)) that are critical for the GTPase reaction lead t o constitutive activation of G(s)-coupled signaling pathways, and such soma tic mutations are found in endocrine tumors, fibrous dysplasia of bone, and the McCune-Albright syndrome. Conversely, heterozygous loss-of-function mu tations may lead to Albright hereditary osteodystrophy (AHO), a disease cha racterized by short stature, obesity, brachydactyly, se ossifications, and mental deficits. Similar mutations are also associated with progressive oss eous heteroplasia. Interestingly, paternal transmission of GNAS1 mutations leads to the AHO phenotype alone (pseudopseudohypoparathyroidism), while ma ternal transmission leads to AHO plus resistance to several hormones (e.g., PTH, TSH) that activate G(s) in their target tissues (pseudohypoparathyroi dism type IA). Studies in G(s)alpha knockout mice demonstrate that G(s)alph a 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 oth er tissues. Disrupting mutations in the maternal allele lead to loss of G(s )alpha expression in proximal tubules and therefore loss of PTH action in t he kidney, while mutations in the paternal allele have little effect on G(s )alpha expression or PTH action. G(s)alpha has recently been shown to be al so imprinted in human pituitary glands. The G(s)alpha gene GNAS1 (as well a s its murine ortholog Gnas) has at least four alternative promoters and fir st exons, leading to the production of alternative gene products including G(s)alpha, XL alphas (a novel G(s)alpha isoform that is expressed only from the paternal allele), and NESP55 (a chromogranin-like protein that is expr essed only from the maternal allele). A fourth alternative promoter and fir st exon (exon 1A) located approximately 2.5 kb upstream of the G,a promoter is normally methylated on the maternal allele and transcriptionally active on the paternal allele. In patients with isolated renal resistance to PTH (pseudohypoparathyroidisin type EB), the exon 1A promoter region has a pate rnal-specific imprinting pattern on both alleles (unmethylated, transcripti onally active), suggesting that this region is critical for the tissue-spec ific imprinting of G(s)alpha. The GNAS1 imprinting defect in pseudohypopara thyroidisin type IB is predicted to decrease G(s)alpha expression in renal proximal tubules. Studies in G(s)alpha knockout mice also demonstrate that this gene is critical in the regulation of lipid and glucose metabolism.