Article

Studies of the regulation and function of the G sα gene Gnas using gene targeting technology

Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20854, USA.
Pharmacology [?] Therapeutics (Impact Factor: 7.75). 08/2007; 115(2):271-291. DOI: 10.1016/j.pharmthera.2007.03.013
Source: PubMed

ABSTRACT The heterotrimeric G protein α-subunit Gsα is ubiquitously expressed and mediates receptor-stimulated intracellular cAMP generation. Its gene Gnas is a complex imprinted gene which uses alternative promoters and first exons to generate other gene products, including the Gsα isoform XLαs and the chromogranin-like protein NESP55, which are specifically expressed from the paternal and maternal alleles, respectively. Gsα itself is imprinted in a tissue-specific manner, being biallelically expressed in most tissues but paternally silenced in a few tissues. Gene targeting of specific Gnas transcripts demonstrates that heterozygous mutation of Gsα on the maternal (but not the paternal) allele leads to early lethality, perinatal subcutaneous edema, severe obesity, and multihormone resistance, while the paternal mutation leads to only mild obesity and insulin resistance. These parent-of-origin differences are the consequence of tissue-specific Gsα imprinting. XLαs deficiency leads to a perinatal suckling defect and a lean phenotype with increased insulin sensitivity. The opposite metabolic effects of Gsα and XLαs deficiency are associated with decreased and increased sympathetic nervous system activity, respectively. NESP55 deficiency has no metabolic consequences. Other gene targeting experiments have shown Gnas to have 2 independent imprinting domains controlled by 2 different imprinting control regions. Tissue-specific Gsα knockout models have identified important roles for Gsα signaling pathways in skeletal development, renal function, and glucose and lipid metabolism. Our present knowledge gleaned from various Gnas gene targeting models are discussed in relation to the pathogenesis of human disorders with mutation or abnormal imprinting of the human orthologue GNAS.

Download full-text

Full-text

Available from: Min Chen, Jul 05, 2015
1 Follower
 · 
83 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: G(s)α is a ubiquitously expressed G protein α-subunit that couples receptors to the generation of intracellular cyclic AMP. The G(s)α gene GNAS is a complex gene that undergoes genomic imprinting, an epigenetic phenomenon that leads to differential expression from the two parental alleles. G(s)α is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in a small number of tissues. Albright hereditary osteodystrophy is a monogenic obesity disorder caused by heterozygous G(s)α mutations but only when the mutations are maternally inherited. Studies in mice indicate a similar parent-of-origin effect on energy and glucose metabolism, with maternal but not paternal mutations leading to obesity, reduced sympathetic nerve activity and energy expenditure, glucose intolerance and insulin resistance, with no primary effect on food intake. These effects result from G(s)α imprinting leading to severe G(s)α deficiency in one or more regions of the central nervous system, and are associated with a specific defect in melanocortins to stimulate sympathetic nerve activity and energy expenditure.
    European journal of pharmacology 06/2011; 660(1):119-24. DOI:10.1016/j.ejphar.2010.10.105 · 2.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The human GNAS gene is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in pituitary, thyroid, renal proximal tubules, and gonads, but is supposed to be biallelically expressed with an equal allelic expression in most other tissues. We analysed allelic expression of Gαs using Pyrosequencing. By genotyping the GNAS T393C polymorphism we quantified mRNA transcripts in lymphoblasts (Ly, n=11), peripheral blood mononuclear cells (PBMC, n=18), mammary adipose tissue (MAT, n=23) and heart tissue (HT, n=44). Allelic expression analysis revealed an unequal allelic expression (ratio maternal/total×100±SEM: 55.7±1% (95% CI 53.4-58.1%) in Ly, 56.1±0.8 (95% CI 54.5-57.7%) in PBMC, 54.5±0.8% (95% CI 53-56.1%) in MAT and 54.1±0.6% (95% CI 53-55.3%) in HT). Maternal ratio differed significantly from the mean (p<0.0001). This phenomenon may be a general feature existing in all tissues.
    Molecular and Cellular Endocrinology 06/2011; 341(1-2):63-70. DOI:10.1016/j.mce.2011.05.032 · 4.24 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In Albright hereditary osteodystrophy, a monogenic obesity disorder linked to heterozygous mutations of G(s)alpha, the G protein that mediates receptor-stimulated cAMP generation, obesity develops only when the mutation is on the maternal allele. Likewise, mice with maternal (but not paternal) germline G(s)alpha mutation develop obesity, insulin resistance, and diabetes. These parent-of-origin effects are due to G(s)alpha imprinting, with preferential expression from the maternal allele in some tissues. As G(s)alpha is ubiquitously expressed, the tissue involved in this metabolic imprinting effect is unknown. Using brain-specific G(s)alpha knockout mice, we show that G(s)alpha imprinting within the central nervous system underlies these effects and that G(s)alpha is imprinted in the paraventricular nucleus of the hypothalamus. Maternal G(s)alpha mutation impaired melanocortin stimulation of energy expenditure but did not affect melanocortin's effect on food intake, suggesting that melanocortins may regulate energy balance in the central nervous system through both G(s)alpha-dependent and -independent pathways.
    Cell metabolism 07/2009; 9(6):548-55. DOI:10.1016/j.cmet.2009.05.004 · 16.75 Impact Factor