Advertisement

G Protein Gsα and GNAS Imprinting

  • Murat BastepeEmail author
Chapter

Abstract

Many hormones, neurotransmitters, and autocrine/paracrine factors exert their actions via the heterotrimeric stimulatory G protein, Gs. This protein mediates receptor-activated stimulation of adenylyl cyclase, which catalyzes the generation of the ubiquitous second messenger cyclic AMP. The α-subunit (Gsα) is critical for the function of the stimulatory G protein and its complete loss leads to embryonic lethality. Moreover, mutations of the gene encoding Gsα, GNAS, lead to several different human diseases. GNAS is a complex imprinted gene. In addition to Gsα, it gives rise to several gene products that show monoallelic expression, including the maternally expressed neuroendocrine secretory protein NESP55 and the paternally expressed extra-large Gsα variant XLαs. Also derived from the paternal GNAS allele are the so-called A/B (also referred to as 1A or 1′) transcript and an antisense transcript (GNAS-AS1), which play regulatory roles in the expression of different GNAS transcripts. In contrast to these monoallelic gene products, Gsα is expressed biallelically in most tissues. The paternal Gsα allele, however, is silenced in a tissue-specific manner, thus limiting Gsα expression levels and, thereby, the actions of certain hormones. The allelic Gsα silencing also plays a role in the development of the phenotypes resulting from GNAS mutations. The mechanisms governing the imprinting of GNAS are incompletely understood, but genetic findings from patients with certain forms of pseudohypoparathyroidism and the study of mouse models point to different cis-acting elements within or nearby GNAS as critical factors.

Keywords

Stimulatory G protein GNAS Cyclic AMP Imprinting DNA methylation 

References

  1. 1.
    Yu S, Yu D, Lee E et al (1998) Variable and tissue-specific hormone resistance in heterotrimeric Gs protein a-subunit (Gsa) knockout mice is due to tissue-specific imprinting of the Gsa gene. Proc Natl Acad Sci U S A 95:8715–8720PubMedPubMedCentralGoogle Scholar
  2. 2.
    Germain-Lee EL, Schwindinger W, Crane JL et al (2005) A mouse model of Albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. Endocrinology 146:4697–4709PubMedGoogle Scholar
  3. 3.
    Chen M, Gavrilova O, Liu J et al (2005) Alternative Gnas gene products have opposite effects on glucose and lipid metabolism. Proc Natl Acad Sci U S A 102:7386–7391PubMedPubMedCentralGoogle Scholar
  4. 4.
    Weinstein LS, Gejman PV, Friedman E et al (1990) Mutations of the Gs alpha-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc Natl Acad Sci U S A 87:8287–8290PubMedPubMedCentralGoogle Scholar
  5. 5.
    Patten JL, Johns DR, Valle D et al (1990) Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright’s hereditary osteodystrophy. N Engl J Med 322:1412–1419PubMedGoogle Scholar
  6. 6.
    Eddy MC, De Beur SM, Yandow SM et al (2000) Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification. J Bone Miner Res 15:2074–2083PubMedGoogle Scholar
  7. 7.
    Linglart A, Carel JC, Garabedian M et al (2002) GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance. J Clin Endocrinol Metab 87:189–197PubMedGoogle Scholar
  8. 8.
    Landis CA, Masters SB, Spada A et al (1989) GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 340:692–696PubMedGoogle Scholar
  9. 9.
    Lyons J, Landis CA, Harsh G et al (1990) Two G protein oncogenes in human endocrine tumors. Science 249:655–659PubMedGoogle Scholar
  10. 10.
    Weinstein LS, Shenker A, Gejman PV et al (1991) Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 325:1688–1695PubMedGoogle Scholar
  11. 11.
    Schwindinger WF, Francomano CA, Levine MA (1992) Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci U S A 89:5152–5156PubMedPubMedCentralGoogle Scholar
  12. 12.
    Liu J, Litman D, Rosenberg M et al (2000) A GNAS1 imprinting defect in pseudohypoparathyroidism type IB. J Clin Invest 106:1167–1174PubMedPubMedCentralGoogle Scholar
  13. 13.
    Bastepe M, Lane AH, Jüppner H (2001) Paternal uniparental isodisomy of chromosome 20q (patUPD20q) – and the resulting changes in GNAS1 methylation – as a plausible cause of pseudohypoparathyroidism. Am J Hum Genet 68:1283–1289PubMedPubMedCentralGoogle Scholar
  14. 14.
    Bastepe M, Pincus JE, Sugimoto T et al (2001) Positional dissociation between the genetic mutation responsible for pseudohypoparathyroidism type Ib and the associated methylation defect at exon A/B: evidence for a long-range regulatory element within the imprinted GNAS1 locus. Hum Mol Genet 10:1231–1241PubMedGoogle Scholar
  15. 15.
    Bourne HR, Sanders DA, McCormick F (1991) The GTPase superfamily: conserved structure and molecular mechanism. Nature 349:117–127PubMedGoogle Scholar
  16. 16.
    Ma YC, Huang J, Ali S et al (2000) Src tyrosine kinase is a novel direct effector of G proteins. Cell 102:635–646PubMedGoogle Scholar
  17. 17.
    Yatani A, Imoto Y, Codina J et al (1988) The stimulatory G protein of adenylyl cyclase, Gs, also stimulates dihydropyridine-sensitive Ca2+ channels. Evidence for direct regulation independent of phosphorylation by cAMP-dependent protein kinase or stimulation by a dihydropyridine agonist. J Biol Chem 263:9887–9895PubMedGoogle Scholar
  18. 18.
    Mattera R, Graziano MP, Yatani A et al (1989) Splice variants of the alpha subunit of the G protein Gs activate both adenylyl cyclase and calcium channels. Science 243:804–807PubMedGoogle Scholar
  19. 19.
    Taylor SS, Buechler JA, Yonemoto W (1990) cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes. Annu Rev Biochem 59:971–1005PubMedGoogle Scholar
  20. 20.
    Bos JL (2006) Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci 31:680–686PubMedGoogle Scholar
  21. 21.
    Sondek J, Lambright DG, Noel JP et al (1994) GTPase mechanism of Gproteins from the 1.7-A crystal structure of transducin alpha-GDP-AIF-4. Nature 372:276–279PubMedGoogle Scholar
  22. 22.
    Coleman DE, Berghuis AM, Lee E et al (1994) Structures of active conformations of Gi alpha 1 and the mechanism of GTP hydrolysis. Science 265:1405–1412PubMedGoogle Scholar
  23. 23.
    Graziano MP, Gilman AG (1989) Synthesis in Escherichia coli of GTPase-deficient mutants of Gs alpha. J Biol Chem 264:15475–15482PubMedGoogle Scholar
  24. 24.
    Wedegaertner PB, Bourne HR, von Zastrow M (1996) Activation-induced subcellular redistribution of Gs alpha. Mol Biol Cell 7:1225–1233PubMedPubMedCentralGoogle Scholar
  25. 25.
    Linder ME, Middleton P, Hepler JR et al (1993) Lipid modifications of G proteins: alpha subunits are palmitoylated. Proc Natl Acad Sci U S A 90:3675–3679PubMedPubMedCentralGoogle Scholar
  26. 26.
    Wedegaertner PB, Bourne HR (1994) Activation and depalmitoylation of Gs alpha. Cell 77:1063–1070PubMedGoogle Scholar
  27. 27.
    Huang C, Duncan JA, Gilman AG et al (1999) Persistent membrane association of activated and depalmitoylated G protein alpha subunits. Proc Natl Acad Sci U S A 96:412–417PubMedPubMedCentralGoogle Scholar
  28. 28.
    Iiri T, Backlund PS Jr, Jones TL et al (1996) Reciprocal regulation of Gs alpha by palmitate and the beta gamma subunit. Proc Natl Acad Sci U S A 93:14592–14597PubMedPubMedCentralGoogle Scholar
  29. 29.
    Evanko DS, Thiyagarajan MM, Siderovski DP et al (2001) Gbeta gamma isoforms selectively rescue plasma membrane localization and palmitoylation of mutant Galphas and Galphaq. J Biol Chem 276:23945–23953PubMedGoogle Scholar
  30. 30.
    Levis MJ, Bourne HR (1992) Activation of the alpha subunit of Gs in intact cells alters its abundance, rate of degradation, and membrane avidity. J Cell Biol 119:1297–1307PubMedGoogle Scholar
  31. 31.
    Bray P, Carter A, Simons C et al (1986) Human cDNA clones for four species of G alpha s signal transduction protein. Proc Natl Acad Sci U S A 83:8893–8897PubMedPubMedCentralGoogle Scholar
  32. 32.
    Kozasa T, Itoh H, Tsukamoto T et al (1988) Isolation and characterization of the human Gsα gene. Proc Natl Acad Sci U S A 85:2081–2085PubMedPubMedCentralGoogle Scholar
  33. 33.
    Robishaw JD, Smigel MD, Gilman AG (1986) Molecular basis for two forms of the G protein that stimulates adenylate cyclase. J Biol Chem 261:9587–9590PubMedGoogle Scholar
  34. 34.
    Sternweis PC, Northup JK, Smigel MD et al (1981) The regulatory component of adenylate cyclase. Purification and properties. J Biol Chem 256:11517–11526PubMedGoogle Scholar
  35. 35.
    Walseth TF, Zhang HJ, Olson LK et al (1989) Increase in Gs and cyclic AMP generation in HIT cells. Evidence that the 45-kDa alpha-subunit of Gs has greater functional activity than the 52-kDa alpha-subunit. J Biol Chem 264:21106–21111PubMedGoogle Scholar
  36. 36.
    Graziano MP, Freissmuth M, Gilman AG (1989) Expression of Gs alpha in Escherichia coli. Purification and properties of two forms of the protein. J Biol Chem 264:409–418PubMedGoogle Scholar
  37. 37.
    Seifert R, Wenzel-Seifert K, Lee TW et al (1998) Different effects of Gsalpha splice variants on beta2-adrenoreceptor-mediated signaling. The beta2-adrenoreceptor coupled to the long splice variant of Gsalpha has properties of a constitutively active receptor. J Biol Chem 273:5109–5116Google Scholar
  38. 38.
    Kvapil P, Novotny J, Svoboda P et al (1994) The short and long forms of the alpha subunit of the stimulatory guanine-nucleotide-binding protein are unequally redistributed during (-)-isoproterenol-mediated desensitization of intact S49 lymphoma cells. Eur J Biochem 226:193–199PubMedGoogle Scholar
  39. 39.
    el Jamali A, Rachdaoui N, Jacquemin C et al (1996) Long-term effect of forskolin on the activation of adenylyl cyclase in astrocytes. J Neurochem 67:2532–2539PubMedGoogle Scholar
  40. 40.
    Bourgeois C, Duc-Goiran P, Robert B et al (1996) G protein expression in human fetoplacental vascularization. Functional evidence for Gs alpha and Gi alpha subunits. J Mol Cell Cardiol 28:1009–1021PubMedGoogle Scholar
  41. 41.
    Crawford JA, Mutchler KJ, Sullivan BE et al (1993) Neural expression of a novel alternatively spliced and polyadenylated Gs alpha transcript. J Biol Chem 268:9879–9885PubMedGoogle Scholar
  42. 42.
    Gejman PV, Weinstein LS, Martinez M et al (1991) Genetic mapping of the Gs-a subunit gene (GNAS1) to the distal long arm of chromosome 20 using a polymorphism detected by denaturing gradient gel electrophoresis. Genomics 9:782–783PubMedGoogle Scholar
  43. 43.
    Rao VV, Schnittger S, Hansmann I (1991) G protein Gs alpha (GNAS 1), the probable candidate gene for Albright hereditary osteodystrophy, is assigned to human chromosome 20q12-q13.2. Genomics 10:257–261PubMedGoogle Scholar
  44. 44.
    Levine MA, Modi WS, O’Brien SJ (1991) Mapping of the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase (GNAS1) to 20q13.2–q13.3 in human by in situ hybridization. Genomics 11:478–479PubMedGoogle Scholar
  45. 45.
    Blatt C, Eversole-Cire P, Cohn VH et al (1988) Chromosomal localization of genes encoding guanine nucleotide-binding protein subunits in mouse and human. Proc Natl Acad Sci U S A 85:7642–7646PubMedPubMedCentralGoogle Scholar
  46. 46.
    Peters J, Beechey CV, Ball ST et al (1994) Mapping studies of the distal imprinting region of mouse chromosome 2. Genet Res 63:169–174PubMedGoogle Scholar
  47. 47.
    Abramowitz J, Grenet D, Birnbaumer M et al (2004) XLalphas, the extra-long form of the alpha-subunit of the Gs G protein, is significantly longer than suspected, and so is its companion Alex. Proc Natl Acad Sci U S A 101:8366–8371PubMedPubMedCentralGoogle Scholar
  48. 48.
    Hayward BE, Moran V, Strain L et al (1998) Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proc Natl Acad Sci U S A 95:15475–15480PubMedPubMedCentralGoogle Scholar
  49. 49.
    Peters J, Wroe SF, Wells CA et al (1999) A cluster of oppositely imprinted transcripts at the Gnas locus in the distal imprinting region of mouse chromosome 2. Proc Natl Acad Sci U S A 96:3830–3835PubMedPubMedCentralGoogle Scholar
  50. 50.
    Ischia R, Lovisetti-Scamihorn P, Hogue-Angeletti R et al (1997) Molecular cloning and characterization of NESP55, a novel chromogranin-like precursor of a peptide with 5-HT1B receptor antagonist activity. J Biol Chem 272:11657–11662PubMedGoogle Scholar
  51. 51.
    Lovisetti-Scamihorn P, Fischer-Colbrie R, Leitner B et al (1999) Relative amounts and molecular forms of NESP55 in various bovine tissues. Brain Res 829:99–106PubMedGoogle Scholar
  52. 52.
    Weiss U, Ischia R, Eder S et al (2000) Neuroendocrine secretory protein 55 (NESP55): alternative splicing onto transcripts of the GNAS gene and posttranslational processing of a maternally expressed protein. Neuroendocrinology 71:177–186PubMedGoogle Scholar
  53. 53.
    Bauer R, Weiss C, Marksteiner J et al (1999) The new chromogranin-like protein NESP55 is preferentially localized in adrenaline-synthesizing cells of the bovine and rat adrenal medulla. Neurosci Lett 263:13–16PubMedGoogle Scholar
  54. 54.
    Plagge A, Isles AR, Gordon E et al (2005) Imprinted Nesp55 influences behavioral reactivity to novel environments. Mol Cell Biol 25:3019–3026PubMedPubMedCentralGoogle Scholar
  55. 55.
    Linglart A, Bastepe M, Jüppner H (2007) Similar clinical and laboratory findings in patients with symptomatic autosomal dominant and sporadic pseudohypoparathyroidism type Ib despite different epigenetic changes at the GNAS locus. Clin Endocrinol (Oxf) 67:822–831Google Scholar
  56. 56.
    Hayward B, Kamiya M, Strain L et al (1998) The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc Natl Acad Sci U S A 95:10038–10043PubMedPubMedCentralGoogle Scholar
  57. 57.
    Li T, Vu TH, Zeng ZL et al (2000) Tissue-specific expression of antisense and sense transcripts at the imprinted Gnas locus. Genomics 69:295–304PubMedGoogle Scholar
  58. 58.
    Michienzi S, Cherman N, Holmbeck K et al (2007) GNAS transcripts in skeletal progenitors: evidence for random asymmetric allelic expression of Gs{alpha}. Hum Mol Genet 16:1921–1930PubMedGoogle Scholar
  59. 59.
    Kehlenbach RH, Matthey J, Huttner WB (1994) XLas is a new type of G protein (Erratum in Nature 1995 375:253). Nature 372:804–809PubMedGoogle Scholar
  60. 60.
    Pasolli H, Klemke M, Kehlenbach R et al (2000) Characterization of the extra-large G protein alpha-subunit XLalphas. I. Tissue distribution and subcellular localization. J Biol Chem 275:33622–33632PubMedGoogle Scholar
  61. 61.
    Plagge A, Gordon E, Dean W et al (2004) The imprinted signaling protein XLalphas is required for postnatal adaptation to feeding. Nat Genet 36:818–826PubMedGoogle Scholar
  62. 62.
    Pasolli H, Huttner W (2001) Expression of the extra-large G protein alpha-subunit XLalphas in neuroepithelial cells and young neurons during development of the rat nervous system. Neurosci Lett 301:119–122PubMedGoogle Scholar
  63. 63.
    Krechowec SO, Burton KL, Newlaczyl AU et al (2012) Postnatal changes in the expression pattern of the imprinted signalling protein XLalphas underlie the changing phenotype of deficient mice. PLoS One 7:e29753PubMedPubMedCentralGoogle Scholar
  64. 64.
    Klemke M, Pasolli H, Kehlenbach R et al (2000) Characterization of the extra-large G protein alpha-subunit XLalphas. II. Signal transduction properties. J Biol Chem 275:33633–33640PubMedGoogle Scholar
  65. 65.
    Bastepe M, Gunes Y, Perez-Villamil B et al (2002) Receptor-mediated adenylyl cyclase activation through XLalphas, the extra-large variant of the stimulatory G protein alpha-subunit. Mol Endocrinol 16:1912–1919PubMedGoogle Scholar
  66. 66.
    Linglart A, Mahon MJ, Kerachian MA et al (2006) Coding GNAS mutations leading to hormone resistance impair in vitro agonist- and cholera toxin-induced adenosine cyclic 3′,5′-monophosphate formation mediated by human XLas. Endocrinology 147:2253–2262PubMedGoogle Scholar
  67. 67.
    Liu Z, Segawa H, Aydin C et al (2011) Transgenic overexpression of the extra-large Gs{alpha} variant XL{alpha}s enhances Gs{alpha}-mediated responses in the mouse renal proximal tubule in vivo. Endocrinology 152:1222–1233PubMedPubMedCentralGoogle Scholar
  68. 68.
    Mariot V, Wu JY, Aydin C et al (2011) Potent constitutive cyclic AMP-generating activity of XLalphas implicates this imprinted GNAS product in the pathogenesis of McCune-Albright syndrome and fibrous dysplasia of bone. Bone 48:312–320PubMedPubMedCentralGoogle Scholar
  69. 69.
    Liu Z, Turan S, Wehbi VL et al (2011) Extra-long Galphas variant XLalphas protein escapes activation-induced subcellular redistribution and is able to provide sustained signaling. J Biol Chem 286:38558–38569PubMedPubMedCentralGoogle Scholar
  70. 70.
    Aydin C, Aytan N, Mahon MJ et al (2009) Extralarge XLαs (XXLαs), a variant of stimulatory G protein alpha-subunit (Gsα), is a distinct, membrane-anchored GNAS product that can mimic Gsα. Endocrinology 150:3567–3575PubMedPubMedCentralGoogle Scholar
  71. 71.
    Klemke M, Kehlenbach RH, Huttner WB (2001) Two overlapping reading frames in a single exon encode interacting proteins–a novel way of gene usage. EMBO J 20:3849–3860PubMedPubMedCentralGoogle Scholar
  72. 72.
    Freson K, Jaeken J, Van Helvoirt M et al (2003) Functional polymorphisms in the paternally expressed XLalphas and its cofactor ALEX decrease their mutual interaction and enhance receptor-mediated cAMP formation. Hum Mol Genet 12:1121–1130PubMedGoogle Scholar
  73. 73.
    Xie T, Plagge A, Gavrilova O et al (2006) The alternative stimulatory G protein alpha-subunit XLalphas is a critical regulator of energy and glucose metabolism and sympathetic nerve activity in adult mice. J Biol Chem 281:18989–18999PubMedPubMedCentralGoogle Scholar
  74. 74.
    Skinner J, Cattanach B, Peters J (2002) The imprinted oedematous-small mutation on mouse chromosome 2 identifies new roles for Gnas and Gnasxl in development. Genomics 80:373PubMedGoogle Scholar
  75. 75.
    Kelly ML, Moir L, Jones L et al (2009) A missense mutation in the non-neural G-protein alpha-subunit isoforms modulates susceptibility to obesity. Int J Obes (Lond) 33:507–518Google Scholar
  76. 76.
    Cheeseman MT, Vowell K, Hough TA et al (2012) A mouse model for osseous heteroplasia. PLoS One 7:e51835PubMedPubMedCentralGoogle Scholar
  77. 77.
    Eaton SA, Williamson CM, Ball ST et al (2012) New mutations at the imprinted Gnas cluster show gene dosage effects of Gsalpha in postnatal growth and implicate XLalphas in bone and fat metabolism but not in suckling. Mol Cell Biol 32:1017–1029PubMedPubMedCentralGoogle Scholar
  78. 78.
    Fernandez-Rebollo E, Maeda A, Reyes M et al (2012) Loss of XLalphas (extra-large alphas) imprinting results in early postnatal hypoglycemia and lethality in a mouse model of pseudohypoparathyroidism Ib. Proc Natl Acad Sci U S A 109:6638–6643PubMedPubMedCentralGoogle Scholar
  79. 79.
    Richard N, Molin A, Coudray N et al (2013) Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLalphas in fetal development. J Clin Endocrinol Metab 98:E1549–E1556PubMedPubMedCentralGoogle Scholar
  80. 80.
    Plagge A, Kelsey G, Germain-Lee EL (2008) Physiological functions of the imprinted Gnas locus and its protein variants Galpha(s) and XLalpha(s) in human and mouse. J Endocrinol 196:193–214PubMedGoogle Scholar
  81. 81.
    Turan S, Bastepe M (2013) The GNAS complex locus and human diseases associated with loss-of-function mutations or epimutations within this imprinted gene. Horm Res Paediatr 80:229–241PubMedGoogle Scholar
  82. 82.
    Swaroop A, Agarwal N, Gruen JR et al (1991) Differential expression of novel Gs alpha signal transduction protein cDNA species. Nucleic Acids Res 19:4725–4729PubMedPubMedCentralGoogle Scholar
  83. 83.
    Liu J, Yu S, Litman D et al (2000) Identification of a methylation imprint mark within the mouse Gnas locus. Mol Cell Biol 20:5808–5817PubMedPubMedCentralGoogle Scholar
  84. 84.
    Ishikawa Y, Bianchi C, Nadal-Ginard B et al (1990) Alternative promoter and 5′ exon generate a novel Gsa mRNA. J Biol Chem 265:8458–8462PubMedGoogle Scholar
  85. 85.
    Puzhko S, Goodyer CG, Mohammad AK et al (2011) Parathyroid hormone signaling via Galphas is selectively inhibited by an NH(2) -terminally truncated Galphas: implications for pseudohypoparathyroidism. J Bone Miner Res 26:2473–2485PubMedPubMedCentralGoogle Scholar
  86. 86.
    Hayward B, Bonthron D (2000) An imprinted antisense transcript at the human GNAS1 locus. Hum Mol Genet 9:835–841PubMedGoogle Scholar
  87. 87.
    Wroe SF, Kelsey G, Skinner JA et al (2000) An imprinted transcript, antisense to Nesp, adds complexity to the cluster of imprinted genes at the mouse Gnas locus. Proc Natl Acad Sci U S A 97:3342–3346PubMedPubMedCentralGoogle Scholar
  88. 88.
    Li T, Vu TH, Ulaner GA et al (2004) Activating and silencing histone modifications form independent allelic switch regions in the imprinted Gnas gene. Hum Mol Genet 13:741–750PubMedGoogle Scholar
  89. 89.
    Campbell R, Gosden CM, Bonthron DT (1994) Parental origin of transcription from the human GNAS1 gene. J Med Genet 31:607–614PubMedPubMedCentralGoogle Scholar
  90. 90.
    Turan S, Fernandez-Rebollo E, Aydin C et al (2013) Postnatal establishment of allelic Galphas silencing as a plausible explanation for delayed onset of parathyroid hormone-resistance due to heterozygous Galphas disruption. J Bone Miner Res. doi: 10.1002/jbmr.2070 Google Scholar
  91. 91.
    Liu J, Erlichman B, Weinstein LS (2003) The stimulatory G protein a-subunit Gsa is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B. J Clin Endocrinol Metabol 88:4336–4341Google Scholar
  92. 92.
    Germain-Lee EL, Ding CL, Deng Z et al (2002) Paternal imprinting of Galpha(s) in the human thyroid as the basis of TSH resistance in pseudohypoparathyroidism type 1a. Biochem Biophys Res Commun 296:67–72PubMedGoogle Scholar
  93. 93.
    Hayward B, Barlier A, Korbonits M et al (2001) Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly. J Clin Invest 107:R31–R36PubMedPubMedCentralGoogle Scholar
  94. 94.
    Mantovani G, Ballare E, Giammona E et al (2002) The gsalpha gene: predominant maternal origin of transcription in human thyroid gland and gonads. J Clin Endocrinol Metab 87:4736–4740PubMedGoogle Scholar
  95. 95.
    Chen M, Wang J, Dickerson KE et al (2009) Central nervous system imprinting of the G protein G(s)alpha and its role in metabolic regulation. Cell Metab 9:548–555PubMedPubMedCentralGoogle Scholar
  96. 96.
    Liu J, Chen M, Deng C et al (2005) Identification of the control region for tissue-specific imprinting of the stimulatory G protein alpha-subunit. Proc Natl Acad Sci U S A 102:5513–5518PubMedPubMedCentralGoogle Scholar
  97. 97.
    Davies AJ, Hughes HE (1993) Imprinting in Albright’s hereditary osteodystrophy. J Med Genet 30:101–103PubMedPubMedCentralGoogle Scholar
  98. 98.
    Jüppner H, Schipani E, Bastepe M et al (1998) The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3. Proc Natl Acad Sci U S A 95:11798–11803PubMedPubMedCentralGoogle Scholar
  99. 99.
    Bastepe M, Fröhlich LF, Hendy GN et al (2003) Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. J Clin Invest 112:1255–1263PubMedPubMedCentralGoogle Scholar
  100. 100.
    Linglart A, Gensure RC, Olney RC et al (2005) A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS. Am J Hum Genet 76:804–814PubMedPubMedCentralGoogle Scholar
  101. 101.
    Richard N, Abeguile G, Coudray N et al (2012) A new deletion ablating NESP55 causes loss of maternal imprint of A/B GNAS and autosomal dominant pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab 97:E863–E867PubMedGoogle Scholar
  102. 102.
    Fröhlich LF, Bastepe M, Ozturk D et al (2007) Lack of Gnas epigenetic changes and pseudohypoparathyroidism type Ib in mice with targeted disruption of syntaxin-16. Endocrinology 148:2925–2935PubMedGoogle Scholar
  103. 103.
    Bastepe M, Fröhlich LF, Linglart A et al (2005) Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type-Ib. Nat Genet 37:25–37PubMedGoogle Scholar
  104. 104.
    Chillambhi S, Turan S, Hwang D-Y et al (2008) Deletion of the GNAS antisense transcript results in parent-of-origin specific GNAS imprinting defects and phenotypes including PTH-resistance (Abstract No. 1052). In: 30th annual meeting of The American Society of Bone and Mineral Research, MontrealGoogle Scholar
  105. 105.
    Chotalia M, Smallwood SA, Ruf N et al (2009) Transcription is required for establishment of germline methylation marks at imprinted genes. Genes Dev 23:105–117PubMedPubMedCentralGoogle Scholar
  106. 106.
    Coombes C, Arnaud P, Gordon E et al (2003) Epigenetic properties and identification of an imprint mark in the Nesp-Gnasxl domain of the mouse Gnas imprinted locus. Mol Cell Biol 23:5475–5488PubMedPubMedCentralGoogle Scholar
  107. 107.
    Williamson CM, Ball ST, Nottingham WT et al (2004) A cis-acting control region is required exclusively for the tissue-specific imprinting of Gnas. Nat Genet 36:894–899PubMedGoogle Scholar
  108. 108.
    Williamson CM, Turner MD, Ball ST et al (2006) Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster. Nat Genet 38:350–355PubMedGoogle Scholar
  109. 109.
    Williamson CM, Ball ST, Dawson C et al (2011) Uncoupling antisense-mediated silencing and DNA methylation in the imprinted Gnas cluster. PLoS Genet 7:e1001347PubMedPubMedCentralGoogle Scholar
  110. 110.
    Fröhlich LF, Mrakovcic M, Steinborn R et al (2010) Targeted deletion of the Nesp55 DMR defines another Gnas imprinting control region and provides a mouse model of autosomal dominant PHP-Ib. Proc Natl Acad Sci U S A 107:9275–9280PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Italia 2015

Authors and Affiliations

  1. 1.Endocrine Unit, Department of MedicineMassachusetts General Hospital, Harvard Medical SchoolBostonUSA

Personalised recommendations