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Gene Review

Gnas  -  GNAS (guanine nucleotide binding protein,...

Mus musculus

Synonyms: 5530400H20Rik, A930027G11Rik, Adenylate cyclase-stimulating G alpha protein, Alternative gene product encoded by XL-exon, C130027O20Rik, ...
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Disease relevance of Gnas


Psychiatry related information on Gnas

  • These results indicate a role of maternally expressed Nesp55 in controlling exploratory behavior and are the first demonstration that imprinted genes affect such a fundamental behavior [6].
  • Behavioral analysis of adult Nesp55 mutants revealed, in three separate tasks, abnormal reactivity to novel environments independent of general locomotor activity and anxiety [6].
  • The relationship between voluntary alcohol consumption and brain monoamine levels was studied in the inbred strains of C57BL/6N, C57BL/6J, A/J, BALB/cA, CBA/N, C3H/He and DBA/2cr mice; the congeneric mouse strain, B10.Br/Sg, and the senescence accelerated mouse (SAM P1, SAM P2) [7].

High impact information on Gnas

  • Uniquely, the Nespas DMR acts on the downstream ICR at exon 1A to regulate tissue-specific imprinting of the Gnas gene [8].
  • This rescues the abnormal phenotype of mice with a maternally derived Gnas mutation [9].
  • Mice with mutations in Gnasxl have poor postnatal growth and survival and a spectrum of phenotypic effects that indicate that XL alpha s controls a number of key postnatal physiological adaptations, including suckling, blood glucose and energy homeostasis [10].
  • We show that in the oocyte, truncated RNAs are produced by RNA polymerase II with 5' ends at the P1 and P2 promoters and 3' ends at two T stretches (sites I and II) near the exon 1/intron 1 junction [11].
  • P2 protein-reactive T-lymphocyte lines from Lewis rats were transduced with a recombinant retrovirus containing the mouse nerve growth factor (NGF) gene [12].

Chemical compound and disease context of Gnas


Biological context of Gnas


Anatomical context of Gnas

  • Gnas is also imprinted in brown and white adipose tissue [20].
  • The in vivo role of Gsalpha in skeletogenesis is largely unknown, because of early embryonic lethality of mice with disruption of Gnas exon 2 (Gnas(E2-/E2-)) and the absence of easily detectable phenotypes in growth plate chondrocytes of heterozygous mutant mice (Gnas(+/E2-)) [1].
  • We now report the generation of murine cell lines that carry homozygous disruption of Gnas exon 2, and are therefore null for endogenous XLalpha(s) and Gs(alpha) (Gnas(E2-/E2-)) [21].
  • Targeted disruption of Gnas in embryonic stem cells [22].
  • Mutational analysis of the Edn3 and Gnas genes will determine whether either gene is responsible for the neural crest deficiencies observed in ls/ls mice [23].

Associations of Gnas with chemical compounds

  • The maximal physiological response to vasopressin (urinary concentrating ability) is normal in both m-/+ and +/p- mice and Gnas is not imprinted in the renal inner medulla (the site of vasopressin action) [20].
  • Here we show Oed-Sml to be a point mutation in Gnas exon 6, resulting in a valine to glutamate substitution at residue 159 (V159E) [24].
  • The gene for alpha-stimulating guanine-nucleotide binding polypeptide, Gnas, has been considered as a candidate for the imprinting effects ascribed to distal mouse Chromosome (Chr) 2 [25].
  • P2 purinoceptor antagonists (suramin, reactive blue 2) inhibited the ATP-induced increase in [(3)H]thymidine incorporation [26].
  • RESULTS: During the initial exposure to ethanol, mice with the targeted disruption of one Gsalpha allele (Gnas) were more sensitive to the sedative effects of ethanol compared with wild-type littermates [2].

Physical interactions of Gnas

  • In reconstitution experiments in vitro, phosphorylation of Gs alpha by immune-complexed pp60c-src resulted in enhanced rates of receptor-mediated guanosine 5'-[gamma-thio]triphosphate (GTP[S]) binding and GTP hydrolysis [Hausdorff, Pitcher, Luttrell, Linder, Kurose, Parsons, Caron and Lefkowitz (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 5720-5724] [27].
  • Thus structural and functional analysis reveals that the P3-4 element is a key regulatory element of P3 that contains two separate binding sites for proteins essential for the basal activity of IGF-II P3 [28].
  • Transgenic mice express the mutant form of the alpha subunit of the adenylate cyclase-coupled G alpha s with mutations at codon 201 (R201H) [29].
  • Intracellular Gs alpha immunoreactive binding sites did not colocalize with gold-conjugated transferrin in cells preincubated with this ligand to mark a classical endocytotic pathway [15].

Enzymatic interactions of Gnas

  • We report here that Gs alpha is phosphorylated on two residues by pp60c-src, namely, Tyr-37 and Tyr-377 [27].

Regulatory relationships of Gnas


Other interactions of Gnas

  • Imprinting of alternative transcripts, Nesp, Gnasxl and Nespas (ref. 13), in the cluster is unaffected [9].
  • Only Edn3 and Gnas did not recombine with the ls mutation [23].
  • Heterozygous disruption of Gnas, the gene encoding the stimulatory G-protein alpha subunit (G(s)alpha), leads to distinct phenotypes depending on whether the maternal (m-/+) or paternal (+/p-) allele is disrupted [34].
  • This review considers the strength of evidence in support of this hypothesis for imprinted genes in four "clusters," associated with the imprinted loci Igf2, Igf2r, callipyge, and Gnas [35].
  • This assignment predicts a location of the murine homologue, Rpn-2, to the syntenic segment on mouse chromosome 2 in close proximity to Ada, Src and Gnas [36].

Analytical, diagnostic and therapeutic context of Gnas


  1. Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Bastepe, M., Weinstein, L.S., Ogata, N., Kawaguchi, H., Jüppner, H., Kronenberg, H.M., Chung, U.I. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  2. The cyclic AMP/protein kinase A signal transduction pathway modulates tolerance to sedative and hypothermic effects of ethanol. Yang, X., Oswald, L., Wand, G. Alcohol. Clin. Exp. Res. (2003) [Pubmed]
  3. Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gs alpha deficiency. Chen, M., Gavrilova, O., Zhao, W.Q., Nguyen, A., Lorenzo, J., Shen, L., Nackers, L., Pack, S., Jou, W., Weinstein, L.S. J. Clin. Invest. (2005) [Pubmed]
  4. Potentiation of beta-adrenergic signaling by gene transfer. Drazner, M.H., Koch, W.J., Lefkowitz, R.J. Proc. Assoc. Am. Physicians (1997) [Pubmed]
  5. Effects of perillyl alcohol on melanoma in the TPras mouse model. Lluria-Prevatt, M., Morreale, J., Gregus, J., Alberts, D.S., Kaper, F., Giaccia, A., Powell, M.B. Cancer Epidemiol. Biomarkers Prev. (2002) [Pubmed]
  6. Imprinted Nesp55 influences behavioral reactivity to novel environments. Plagge, A., Isles, A.R., Gordon, E., Humby, T., Dean, W., Gritsch, S., Fischer-Colbrie, R., Wilkinson, L.S., Kelsey, G. Mol. Cell. Biol. (2005) [Pubmed]
  7. Reexamination of the relationship between alcohol preference and brain monoamines in inbred strains of mice including senescence-accelerated mice. Yoshimoto, K., Komura, S. Pharmacol. Biochem. Behav. (1987) [Pubmed]
  8. Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster. Williamson, C.M., Turner, M.D., Ball, S.T., Nottingham, W.T., Glenister, P., Fray, M., Tymowska-Lalanne, Z., Plagge, A., Powles-Glover, N., Kelsey, G., Maconochie, M., Peters, J. Nat. Genet. (2006) [Pubmed]
  9. A cis-acting control region is required exclusively for the tissue-specific imprinting of Gnas. Williamson, C.M., Ball, S.T., Nottingham, W.T., Skinner, J.A., Plagge, A., Turner, M.D., Powles, N., Hough, T., Papworth, D., Fraser, W.D., Maconochie, M., Peters, J. Nat. Genet. (2004) [Pubmed]
  10. The imprinted signaling protein XL alpha s is required for postnatal adaptation to feeding. Plagge, A., Gordon, E., Dean, W., Boiani, R., Cinti, S., Peters, J., Kelsey, G. Nat. Genet. (2004) [Pubmed]
  11. Sequence requirements for premature termination of transcription in the human c-myc gene. Bentley, D.L., Groudine, M. Cell (1988) [Pubmed]
  12. Gene transfer through the blood-nerve barrier: NGF-engineered neuritogenic T lymphocytes attenuate experimental autoimmune neuritis. Kramer, R., Zhang, Y., Gehrmann, J., Gold, R., Thoenen, H., Wekerle, H. Nat. Med. (1995) [Pubmed]
  13. Propranolol prevents enhanced stress signaling in Gs alpha cardiomyopathy: potential mechanism for beta-blockade in heart failure. Karoor, V., Vatner, S.F., Takagi, G., Yang, G., Thaisz, J., Sadoshima, J., Vatner, D.E. J. Mol. Cell. Cardiol. (2004) [Pubmed]
  14. Antisense oligodeoxynucleotides to GS protein alpha-subunit sequence accelerate differentiation of fibroblasts to adipocytes. Wang, H.Y., Watkins, D.C., Malbon, C.C. Nature (1992) [Pubmed]
  15. Immunoelectron microscopic identification of cytoplasmic and nuclear Gs alpha in S49 lymphoma cells. Saffitz, J.E., Nash, J.A., Green, K.G., Luke, R.A., Ransnas, L.A., Insel, P.A. FASEB J. (1994) [Pubmed]
  16. Chronic ethanol treatment increases expression of inhibitory G-proteins and reduces adenylylcyclase activity in the central nervous system of two lines of ethanol-sensitive mice. Wand, G.S., Diehl, A.M., Levine, M.A., Wolfgang, D., Samy, S. J. Biol. Chem. (1993) [Pubmed]
  17. Transcriptional activation of Gs alpha expression by retinoic acid and parathyroid hormone-related protein in F9 teratocarcinoma cells. Chan, S.D., Strewler, G.J., Nissenson, R.A. J. Biol. Chem. (1990) [Pubmed]
  18. Alternative Gnas gene products have opposite effects on glucose and lipid metabolism. Chen, M., Gavrilova, O., Liu, J., Xie, T., Deng, C., Nguyen, A.T., Nackers, L.M., Lorenzo, J., Shen, L., Weinstein, L.S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  19. An imprinted transcript, antisense to Nesp, adds complexity to the cluster of imprinted genes at the mouse Gnas locus. Wroe, S.F., Kelsey, G., Skinner, J.A., Bodle, D., Ball, S.T., Beechey, C.V., Peters, J., Williamson, C.M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  20. Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha-subunit (Gsalpha) knockout mice is due to tissue-specific imprinting of the gsalpha gene. Yu, S., Yu, D., Lee, E., Eckhaus, M., Lee, R., Corria, Z., Accili, D., Westphal, H., Weinstein, L.S. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  21. Receptor-mediated adenylyl cyclase activation through XLalpha(s), the extra-large variant of the stimulatory G protein alpha-subunit. Bastepe, M., Gunes, Y., Perez-Villamil, B., Hunzelman, J., Weinstein, L.S., Jüppner, H. Mol. Endocrinol. (2002) [Pubmed]
  22. Targeted disruption of Gnas in embryonic stem cells. Schwindinger, W.F., Reese, K.J., Lawler, A.M., Gearhart, J.D., Levine, M.A. Endocrinology (1997) [Pubmed]
  23. A high-resolution linkage map of the lethal spotting locus: a mouse model for Hirschsprung disease. Pavan, W.J., Liddell, R.A., Wright, A., Thibaudeau, G., Matteson, P.G., McHugh, K.M., Siracusa, L.D. Mamm. Genome (1995) [Pubmed]
  24. The imprinted oedematous-small mutation on mouse chromosome 2 identifies new roles for Gnas and Gnasxl in development. Skinner, J.A., Cattanach, B.M., Peters, J. Genomics (2002) [Pubmed]
  25. Glomerular-specific imprinting of the mouse gsalpha gene: how does this relate to hormone resistance in albright hereditary osteodystrophy? Williamson, C.M., Schofield, J., Dutton, E.R., Seymour, A., Beechey, C.V., Edwards, Y.H., Peters, J. Genomics (1996) [Pubmed]
  26. ATP Stimulates Mouse Embryonic Stem Cell Proliferation via Protein Kinase C, Phosphatidylinositol 3-Kinase/Akt, and Mitogen-Activated Protein Kinase Signaling Pathways. Heo, J.S., Han, H.J. Stem Cells (2006) [Pubmed]
  27. Identification of the in vitro phosphorylation sites on Gs alpha mediated by pp60c-src. Moyers, J.S., Linder, M.E., Shannon, J.D., Parsons, S.J. Biochem. J. (1995) [Pubmed]
  28. Identification of a key regulatory element for the basal activity of the human insulin-like growth factor II gene promoter P3. Rietveld, L.E., Holthuizen, P.E., Sussenbach, J.S. Biochem. J. (1997) [Pubmed]
  29. Targeted oncogenesis in the thyroid of transgenic mice. Feunteun, J., Michiels, F., Rochefort, P., Caillou, B., Talbot, M., Fournes, B., Mercken, L., Schlumberger, M., Monier, R. Horm. Res. (1997) [Pubmed]
  30. Increased interleukin-6 production in mouse osteoblastic MC3T3-E1 cells expressing activating mutant of the stimulatory G protein. Motomura, T., Kasayama, S., Takagi, M., Kurebayashi, S., Matsui, H., Hirose, T., Miyashita, Y., Yamauchi-Takihara, K., Yamamoto, T., Okada, S., Kishimoto, T. J. Bone Miner. Res. (1998) [Pubmed]
  31. Regulation of cellular Gs alpha levels and basal adenylyl cyclase activity by expression of the beta 2-adrenoceptor in neuroblastoma cell lines. Milligan, G., Kim, G.D., Mullaney, I., Adie, E.J. Mol. Cell. Biochem. (1995) [Pubmed]
  32. Deletion within the amino-terminal region of Gs alpha impairs its ability to interact with beta gamma subunits and to activate adenylate cyclase. Journot, L., Pantaloni, C., Bockaert, J., Audigier, Y. J. Biol. Chem. (1991) [Pubmed]
  33. Suppression of Ras-induced transformation of NIH 3T3 cells by activated G alpha s. Chen, J., Iyengar, R. Science (1994) [Pubmed]
  34. Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism. Yu, S., Gavrilova, O., Chen, H., Lee, R., Liu, J., Pacak, K., Parlow, A.F., Quon, M.J., Reitman, M.L., Weinstein, L.S. J. Clin. Invest. (2000) [Pubmed]
  35. Genomic imprinting and kinship: how good is the evidence? Haig, D. Annu. Rev. Genet. (2004) [Pubmed]
  36. Mapping of the ribophorin II (RPN II) gene to human chromosome 20q12-q13.1 by in-situ hybridization. Löffler, C., Rao, V.V., Hansmann, I. Hum. Genet. (1991) [Pubmed]
  37. Activating and silencing histone modifications form independent allelic switch regions in the imprinted Gnas gene. Li, T., Vu, T.H., Ulaner, G.A., Yang, Y., Hu, J.F., Hoffman, A.R. Hum. Mol. Genet. (2004) [Pubmed]
  38. Overexpression of Gs alpha protein in the hearts of transgenic mice. Gaudin, C., Ishikawa, Y., Wight, D.C., Mahdavi, V., Nadal-Ginard, B., Wagner, T.E., Vatner, D.E., Homcy, C.J. J. Clin. Invest. (1995) [Pubmed]
  39. Apoptosis of cardiac myocytes in Gsalpha transgenic mice. Geng, Y.J., Ishikawa, Y., Vatner, D.E., Wagner, T.E., Bishop, S.P., Vatner, S.F., Homcy, C.J. Circ. Res. (1999) [Pubmed]
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