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Vol. 113, No. 1-4, 2006
Issue release date: March 2006

Imprinting the Gnas locus

Plagge A. · Kelsey G.
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Gnas is an enigmatic and rather complex imprinted gene locus. A single transcription unit encodes three, and possibly more, distinct proteins. These are determined by overlapping transcripts from alternative promoters with different patterns of imprinting. The canonical Gnas transcript codes for Gsα, a highly conserved signalling protein and an essential intermediate in growth, differentiation and homeostatic pathways. Monoallelic expression of Gnas is highly tissue-restricted. The alternative transcripts encode XLαs, an unusual variant of Gsα, and the chromogranin-like protein Nesp55. These transcripts are expressed specifically from the paternal and maternal chromosomes, respectively. Their existence in the Gnas locus might imply functional connections amongst them or with Gsα. In this review, we consider how imprinting of Gnas was discovered, the phenotypic consequences of mutations in each of the gene products, both in the mouse and human, and provide some conjectures to explain why this elaborate imprinted locus has evolved in this manner in mammals.

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  1. Abramowitz J, Grenet D, Birnbaumer M, Torres HN, Birnbaumer L: 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 USA 101:8366–8371 (2004).
  2. Aldred MA, Trembath RC: Activating and inactivating mutations in the human GNAS1 gene. Hum Mutat 16:183–189 (2000).
  3. Aldred MA, Aftimos S, Hall C, Waters KS, Thakker RV, Trembath RC, Brueton L: Constitutional deletion of chromosome 20q in two patients affected with Albright hereditary osteodystrophy. Am J Med Genet 113:167–172 (2002).
  4. Bastepe M, Gunes Y, Perez-Villamil B, Hunzelman J, Weinstein LS, Jüppner H: Receptor-mediated adenylyl cyclase activation through XLalpha(s), the extra-large variant of the stimulatory G protein alpha-subunit. Mol Endocrinol 16:1912–1919 (2002).
  5. Bastepe M, Weinstein LS, Ogata N, Kawaguchi H, Jüppner H, Kronenberg HM, Chung UI: Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Proc Natl Acad Sci USA 101:14794–14799 (2004).
  6. Bastepe M, Fröhlich LF, Linglart A, Abu-Zahra HS, Tojo K, Ward LM, Jüppner H: Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nat Genet 37:25–27 (2005).
  7. Bauer R, Ischia R, Marksteiner J, Kapeller I, Fischer-Colbrie R: Localization of neuroendocrine secretory protein 55 messenger RNA in the rat brain. Neuroscience 91:685–694 (1999a).
  8. Bauer R, Weiss C, Marksteiner J, Doblinger A, Fischer-Colbrie R, Laslop A: The new chromogranin-like protein NESP55 is preferentially localized in adrenaline-synthesizing cells of the bovine and rat adrenal medulla. Neurosci Lett 263:13–16 (1999b).
  9. Beaudet AL, Jiang YH: A rheostat model for a rapid and reversible form of imprinting-dependent evolution. Am J Hum Genet 70:1389–1397 (2002).
  10. Campbell R, Gosden CM, Bonthron DT: Parental origin of transcription from the human GNAS1 gene. J Med Genet 31:607–614 (1994).
  11. Cattanach BM, Kirk M: Differential activity of maternally and paternally derived chromosome regions in mice. Nature 315:496–498 (1985).
  12. Cattanach BM, Peters J, Ball S, Rasberry C: Two imprinted gene mutations: three phenotypes. Hum Mol Genet 9:2263–2273 (2000).
  13. Chan I, Hamada T, Hardman C, McGrath JA, Child FJ: Progressive osseous heteroplasia resulting from a new mutation in the GNAS1 gene. Clin Exp Dermatol 29:77–80 (2004).
  14. Chen M, Haluzik M, Wolf NJ, Lorenzo J, Dietz KR, Reitman ML, Weinstein LS: Increased insulin sensitivity in paternal Gnas knockout mice is associated with increased lipid clearance. Endocrinology 145:4094–4102 (2004).
  15. Chen M, Gavrilova O, Liu J, Xie T, Deng C, Nguyen AT, Nackers LM, Lorenzo J, Shen L, Weinstein LS: Alternative Gnas gene products have opposite effects on glucose and lipid metabolism. Proc Natl Acad Sci USA 102:7386–7391 (2005).
  16. Chudoba I, Franke Y, Senger G, Sauerbrei G, Demuth S, Beensen V, Neumann A, Hansmann I, Claussen U: Maternal UPD 20 in a hyperactive child with severe growth retardation. Eur J Hum Genet 7:533–540 (1999).
  17. Constância M, Kelsey G, Reik W: Resourceful imprinting. Nature 432:53–57 (2004).
  18. Crawford JA, Mutchler KJ, Sullivan BE, Lanigan TM, Clark MS, Russo AF: Neural expression of a novel alternatively spliced and polyadenylated Gs alpha transcript. J Biol Chem 268:9879–9885 (1993).
  19. Davies SJ, Hughes HE: Imprinting in Albright’s hereditary osteodystrophy. J Med Genet 30:101–103 (1993).
  20. de la Casa-Esperon E, Sapienza C: Natural selection and the evolution of genome imprinting. Annu Rev Genet 37:349–370 (2003).
  21. Dumas JJ, Lambright DG: Gs alpha meets its tar get – shedding light on a key signal transduction event. Structure 6:407–411 (1998).
  22. Eddy MC, De Beur SM, Yandow SM, McAlister WH, Shore EM, Kaplan FS, Whyte MP, Levine MA: Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification. J Bone Miner Res 15:2074–2083 (2000).
  23. Eggermann T, Mergenthaler S, Eggermann K, Albers A, Linnemann K, Fusch C, Ranke MB, Wollmann HA: Identification of interstitial maternal uniparental disomy (UPD) (14) and complete maternal UPD (20) in a cohort of growth retarded patients. J Med Genet 38:86–89 (2001).
  24. Fischer JA, Egert F, Werder E, Born W: An inherited mutation associated with functional deficiency of the alpha-subunit of the guanine nucleotide-binding protein Gs in pseudo- and pseudopseudohypoparathyroidism. J Clin Endocrinol Metab 83:935–938 (1998).
  25. Fischer-Colbrie R, Eder S, Lovisetti-Scamihorn P, Becker A, Laslop A: Neuroendocrine secretory protein 55: a novel marker for the constitutive secretory pathway. Ann NY Acad Sci 971:317–322 (2002).
  26. Freson K, Jaeken J, Van Helvoirt M, de Zegher F, Wittevrongel C, Thys C, Hoylaerts MF, Vermylen J, Van Geet C: Functional polymorphisms in the paternally expressed XLalphas and its cofactor ALEX decrease their mutual interaction and enhance receptor-mediated cAMP formation. Hum Mol Genet 12:1121–1130 (2003).
  27. Genevieve D, Sanlaville D, Faivre L, Kottler ML, Jambou M, Gosset P, Boustani-Samara D, Pinto G, Ozilou C, Abeguile G, Munnich A, Romana S, Raoul O, Cormier-Daire V, Vekemans M: Paternal deletion of the GNAS imprinted locus (including Gnasxl) in two girls presenting with severe pre- and post-natal growth retardation and intractable feeding difficulties. Eur J Hum Genet 13:1033–1039 (2005).
  28. Germain-Lee EL, Ding CL, Deng Z, Crane JL, Saji M, Ringel MD, Levine MA: Paternal imprinting of Galpha(s) in the human thyroid as the basis of TSH resistance in pseudohypoparathyroidism type 1a. Biochem Biophys Res Commun 296:67–72 (2002).
  29. Germain-Lee EL, Schwindinger W, Crane JL, Zewdu R, Zweifel LS, Wand G, Huso DL, Saji M, Ringel MD, Levine MA: A mouse model of Albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. Endocrinology 146:4697–4709 (2005).
  30. Haig D: Evolutionary conflicts in pregnancy and calcium metabolism–a review. Placenta 25 Suppl A:S10–S15 (2004a).
  31. Haig D: Genomic imprinting and kinship: how good is the evidence? Annu Rev Genet 38:553–585 (2004b).
  32. Hayward BE, Bonthron DT: An imprinted antisense transcript at the human GNAS1 locus. Hum Mol Genet 9:835–841 (2000).
  33. Hayward BE, Kamiya M, Strain L, Moran V, Campbell R, Hayashizaki Y, Bonthron DT: The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc Natl Acad Sci USA 95:10038–10043 (1998a).
  34. Hayward BE, Moran V, Strain L, Bonthron DT: Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proc Natl Acad Sci USA 95:15475–15480 (1998b).
  35. Hayward BE, Barlier A, Korbonits M, Grossman AB, Jacquet P, Enjalbert A, Bonthron DT: Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly. J Clin Invest 107:R31–R36 (2001).
  36. Holmes R, Williamson C, Peters J, Denny P, Wells C: A comprehensive transcript map of the mouse Gnas imprinted complex. Genome Res 13:1410–1415 (2003).
  37. Hurst LD: Evolutionary theories of genomic imprinting, in Reik W, Surani A (eds): Genomic Imprinting, pp 211–237 (IRL Press, Oxford 1997).
  38. Ischia R, Lovisetti-Scamihorn P, Hogue-Angeletti R, Wolkersdorfer M, Winkler H, Fischer-Colbrie R: Molecular cloning and characterization of NESP55, a novel chromogranin-like precursor of a peptide with 5-HT1B receptor antagonist activity. J Biol Chem 272:11657–11662 (1997).
  39. Ishikawa Y, Bianchi C, Nadal-Ginard B, Homcy CJ: Alternative promoter and 5′ exon generate a novel Gs alpha mRNA. J Biol Chem 265:8458–8462 (1990).
  40. Isles AR, Baum MJ, Ma D, Szeto A, Keverne EB, Allen ND: A possible role for imprinted genes in inbreeding avoidance and dispersal from the natal area in mice. Proc R Soc Lond B Biol Sci 269:665–670 (2002).
  41. Jüppner H: The genetic basis of progressive osseous heteroplasia. New Engl J Med 346:128–130 (2002).
  42. Kehlenbach RH, Matthey J, Huttner WB: XL alpha s is a new type of G protein. Nature 372:804–809 (1994).
  43. Kelsey G, Bodle D, Miller HJ, Beechey CV, Coombes C, Peters J, Williamson CM: Identification of imprinted loci by methylation-sensitive representational difference analysis: application to mouse distal chromosome 2. Genomics 62:129–138 (1999).
  44. Klemke M, Pasolli HA, Kehlenbach RH, Offermanns S, Schultz G, Huttner WB: Characterization of the extra-large G protein alpha-subunit XLalphas. II. Signal transduction properties. J Biol Chem 275:33633–33640 (2000).
  45. Klemke M, Kehlenbach RH, Huttner WB: Two overlapping reading frames in a single exon encode interacting proteins–a novel way of gene usage. EMBO J 20:3849–3860 (2001).
  46. Li JY, Lovisetti-Scamihorn P, Fischer-Colbrie R, Winkler H, Dahlstrom A: Distribution and intraneuronal trafficking of a novel member of the chromogranin family, NESP55, in the rat peripheral nervous system. Neuroscience 110:731–745 (2002).
  47. Li T, Vu TH, Zeng ZL, Nguyen BT, Hayward BE, Bonthron DT, Hu JF, Hoffman AR: Tissue-specific expression of antisense and sense transcripts at the imprinted Gnas locus. Genomics 69:295–304 (2000).
  48. Liu J, Yu S, Litman D, Chen W, Weinstein LS: Identification of a methylation imprint mark within the mouse Gnas locus. Mol Cell Biol 20:5808–5817 (2000).
  49. Lovisetti-Scamihorn P, Fischer-Colbrie R, Leitner B, Scherzer G, Winkler H: Relative amounts and molecular forms of NESP55 in various bovine tissues. Brain Res 829:99–106 (1999).
  50. Mantovani G, Ballare E, Giammona E, Beck-Peccoz P, Spada A: The gsalpha gene: predominant maternal origin of transcription in human thyroid gland and gonads. J Clin Endocrinol Metab 87:4736–4740 (2002).
  51. Mantovani G, Bondioni S, Locatelli M, Pedroni C, Lania AG, Ferrante E, Filopanti M, Beck-Peccoz P, Spada A: Biallelic expression of the Gsalpha gene in human bone and adipose tissue. J Clin Endocrinol Metab 89:6316–6319 (2004).
  52. Moore T, Haig D: Genomic imprinting in mammalian development: a parental tug-of-war. Trends Genet 7:45–49 (1991).
  53. Morison IM, Ramsay JP, Spencer HG: A census of mammalian imprinting. Trends Genet 21:457–465 (2005).
  54. Nekrutenko A, Wadhawan S, Goetting-Minesky P, Makova KD: Oscillating evolution of a mammalian locus with overlapping reading frames: an XLalphas/ALEX Relay. PLoS Genet 1:e18 (2005).
  55. Pasolli HA, Klemke M, Kehlenbach RH, Wang Y, Huttner WB: Characterization of the extra-large G protein alpha-subunit XLalphas. I. Tissue distribution and subcellular localization. J Biol Chem 275:33622–33632 (2000).
  56. Pasolli HA, Huttner WB: 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 301:119–122 (2001).
  57. Patten JL, Johns DR, Valle D, Eil C, Gruppuso PA, Steele G, Smallwood PM, Levine MA: Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright’s hereditary osteodystrophy. New Engl J Med 322:1412–1419 (1990).
  58. Peters J, Wroe SF, Wells CA, Miller HJ, Bodle D, Beechey CV, Williamson CM, Kelsey G: A cluster of oppositely imprinted transcripts at the Gnas locus in the distal imprinting region of mouse chromosome 2. Proc Natl Acad Sci USA 96:3830–3835 (1999).
  59. Peters J, Holmes R, Monk D, Beechey CV, Moore GE, Williamson CM: Imprinting control within the compact Gnas locus. Cytogenet Genome Res 113:194–201 (2006).

    External Resources

  60. Plagge A, Gordon E, Dean W, Boiani R, Cinti S, Peters J, Kelsey G: The imprinted signaling protein XL alpha s is required for postnatal adaptation to feeding. Nat Genet 36:818–826 (2004).
  61. Plagge A, Isles AR, Gordon E, Humby T, Dean W, Gritsch S, Fischer-Colbrie R, Wilkinson LS, Kelsey G: Imprinted Nesp55 influences behavioral reactivity to novel environments. Mol Cell Biol 25:3019–3026 (2005).
  62. Reik W, Constância M, Fowden A, Anderson N, Dean W, Ferguson-Smith A, Tycko B, Sibley C: Regulation of supply and demand for maternal nutrients in mammals by imprinted genes. J Physiol 547:35–44 (2003).
  63. Sakamoto A, Chen M, Kobayashi T, Kronenberg HM, Weinstein LS: Chondrocyte-specific knockout of the G protein G(s)alpha leads to epiphyseal and growth plate abnormalities and ectopic chondrocyte formation. J Bone Miner Res 20:663–671 (2005a).
  64. Sakamoto A, Chen M, Nakamura T, Xie T, Karsenty G, Weinstein LS: Deficiency of the G-protein alpha-subunit G(s)alpha in osteoblasts leads to differential effects on trabecular and cortical bone. J Biol Chem 280:21369–21375 (2005b).
  65. Salafsky IS, MacGregor SN, Claussen U, von Eggeling F: Maternal UPD 20 in an infant from a pregnancy with mosaic trisomy 20. Prenat Diagn 21:860–863 (2001).
  66. Sara SJ, Dyon-Laurent C, Herve A: Novelty seeking behavior in the rat is dependent upon the integrity of the noradrenergic system. Brain Res Cogn Brain Res 2:181–187 (1995).
  67. Shore EM, Ahn J, Jan de Beur S, Li M, Xu M, Gardner RJ, Zasloff MA, Whyte MP, Levine MA, Kaplan FS: Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med 346:99–106 (2002).
  68. Skinner JA, Cattanach BM, Peters J: The imprinted oedematous-small mutation on mouse chromosome 2 identifies new roles for Gnas and Gnasxl in development. Genomics 80:373–375 (2002).
  69. Trivers R, Burt A: Kinship and genomic imprinting, in Ohlsson R (ed): Genomic Imprinting – An Interdisciplinary Approach, pp 1–21 (Springer, Berlin 1999).
  70. Tycko B, Morison IM: Physiological functions of imprinted genes. J Cell Physiol 192:245–258 (2002).
  71. Ugur O, Jones TL: A proline-rich region and nearby cysteine residues target XLalphas to the Golgi complex region. Mol Biol Cell 11:1421–1432 (2000).
  72. Velissariou V, Antoniadi T, Gyftodimou J, Bakou K, Grigoriadou M, Christopoulou S, Hatzipouliou A, Donoghue J, Karatzis P, Katsarou E, Petersen MB: Maternal uniparental isodisomy 20 in a foetus with trisomy 20 mosaicism: clinical, cytogenetic and molecular analysis. Eur J Hum Genet 10:694–698 (2002).
  73. Weinstein LS, Yu S, Warner DR, Liu J: Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr Rev 22:675–705 (2001).
  74. Wilkins JF, Haig D: What good is genomic imprinting: the function of parent-specific gene expression. Nat Rev Genet 4:359–368 (2003).
  75. Williamson CM, Schofield J, Dutton ER, Seymour A, Beechey CV, Edwards YH, Peters J: Glomerular-specific imprinting of the mouse gsalpha gene: how does this relate to hormone resistance in Albright hereditary osteodystrophy? Genomics 36:280–287 (1996).
  76. Williamson CM, Beechey CV, Papworth D, Wroe SF, Wells CA, Cobb L, Peters J: Imprinting of distal mouse chromosome 2 is associated with phenotypic anomalies in utero. Genet Res 72:255–265 (1998).
  77. Williamson CM, Skinner JA, Kelsey G, Peters J: Alternative non-coding splice variants of Nespas, an imprinted gene antisense to Nesp in the Gnas imprinting cluster. Mamm Genome 13:74–79 (2002).
  78. Williamson CM, Ball ST, Nottingham WT, Skinner JA, Plagge A, Turner MD, Powles N, Hough T, Papworth D, Fraser WD, Maconochie M, Peters J: A cis-acting control region is required exclusively for the tissue-specific imprinting of Gnas. Nat Genet 36:894–899 (2004).
  79. Wilson LC, Oude Luttikhuis ME, Clayton PT, Fraser WD, Trembath RC: Parental origin of Gs alpha gene mutations in Albright’s hereditary osteodystrophy. J Med Genet 31:835–839 (1994).
  80. Wroe SF, Kelsey G, Skinner JA, Bodle D, Ball ST, Beechey CV, Peters J, Williamson CM: An imprinted transcript, antisense to Nesp, adds complexity to the cluster of imprinted genes at the mouse Gnas locus. Proc Natl Acad Sci USA 97:3342–3346 (2000).
  81. Yu S, Yu D, Lee E, Eckhaus M, Lee R, Corria Z, Accili D, Westphal H, Weinstein LS: 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. Proc Natl Acad Sci USA 95:8715–8720 (1998).
  82. Yu S, Gavrilova O, Chen H, Lee R, Liu J, Pacak K, Parlow AF, Quon MJ, Reitman ML, Weinstein LS: Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism. J Clin Invest 105:615–623 (2000).
  83. Yu S, Castle A, Chen M, Lee R, Takeda K, Weinstein LS: Increased insulin sensitivity in Gsalpha knockout mice. J Biol Chem 276:19994–19998 (2001).
  84. Zheng H, Radeva G, McCann JA, Hendy GN, Goodyer CG: Galphas transcripts are biallelically expressed in the human kidney cortex: implications for pseudohypoparathyroidism type 1b. J Clin Endocrinol Metab 86:4627–4629 (2001).

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