Skip to main content

Advertisement

SpringerLink
Log in

GNAS Spectrum of Disorders

  • Rare Bone Disease (CB Langman and E Shore, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

The GNAS complex locus encodes the alpha-subunit of the stimulatory G protein (Gsα), a ubiquitous signaling protein mediating the actions of many hormones, neurotransmitters, and paracrine/autocrine factors via generation of the second messenger cAMP. GNAS gives rise to other gene products, most of which exhibit exclusively monoallelic expression. In contrast, Gsα is expressed biallelically in most tissues; however, paternal Gsα expression is silenced in a small number of tissues through as-yet-poorly understood mechanisms that involve differential methylation within GNAS. Gsα-coding GNAS mutations that lead to diminished Gsα expression and/or function result in Albright’s hereditary osteodystrophy (AHO) with or without hormone resistance, i.e., pseudohypoparathyroidism type-Ia/Ic and pseudo-pseudohypoparathyroidism, respectively. Microdeletions that alter GNAS methylation and, thereby, diminish Gsα expression in tissues in which the paternal Gsα allele is normally silenced also cause hormone resistance, which occurs typically in the absence of AHO, a disorder termed pseudohypoparathyroidism type-Ib. Mutations of GNAS that cause constitutive Gsα signaling are found in patients with McCune-Albright syndrome, fibrous dysplasia of bone, and different endocrine and non-endocrine tumors. Clinical features of these diseases depend significantly on the parental allelic origin of the GNAS mutation, reflecting the tissue-specific paternal Gsα silencing. In this article, we review the pathogenesis and the phenotypes of these human diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Blatt C, Eversole-Cire P, Cohn VH, et al. Chromosomal localization of genes encoding guanine nucleotide-binding protein subunits in mouse and human. Proc Natl Acad Sci U S A. 1988;85:7642–46.

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Kehlenbach RH, Matthey J, Huttner WB. XL alpha s is a new type of G protein. Nature. 1994;372:804–9.

    CAS  PubMed  Google Scholar 

  3. Ischia R, Lovisetti-Scamihorn P, Hogue-Angeletti R, et al. Molecular cloning and characterization of NESP55, a novel chromogranin-like precursor of a peptide with 5-HT1B receptor antagonist activity. J Biol Chem. 1997;272:11657–62.

    CAS  PubMed  Google Scholar 

  4. Ishikawa Y, Bianchi C, Nadal-Ginard B, et al. Alternative promoter and 5' exon generate a novel Gsα mRNA. J Biol Chem. 1990;265:8458–62.

    CAS  PubMed  Google Scholar 

  5. Swaroop A, Agarwal N, Gruen JR, et al. Differential expression of novel Gs alpha signal transduction protein cDNA species. Nucleic Acids Res. 1991;19:4725–29.

    PubMed Central  CAS  PubMed  Google Scholar 

  6. Puzhko S, Goodyer C, Kerachian M, et al. Parathyroid hormone signaling via Gαs is selectively inhibited by an NH2-terminally truncated Gαs: implications for pseudohypoparathyroidism. J Bone Miner Res. 2011;26:2473–85.

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Hayward B, Bonthron D. An imprinted antisense transcript at the human GNAS1 locus. Hum Mol Genet. 2000;9:835–41.

    CAS  PubMed  Google Scholar 

  8. Wroe SF, Kelsey G, Skinner JA, et al. 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. 2000;97:3342–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  9. Barlow DP, Bartolomei MS. Genomic imprinting in mammals. Cold Spring Harb Perspect Biol. 2014 Feb 1;6(2). pii: a018382. doi: 10.1101/cshperspect.a018382.

  10. Bastepe M. The GNAS locus: quintessential complex gene encoding Gsalpha, XLalphas, and other imprinted transcripts. Curr Genomics. 2007;8:398–414.

    PubMed Central  CAS  PubMed  Google Scholar 

  11. Peters J, Williamson CM. Control of imprinting at the Gnas cluster. Adv Exp Med Biol. 2008;626:16–26.

    CAS  PubMed  Google Scholar 

  12. Plagge A, Kelsey G, Germain-Lee EL. Physiological functions of the imprinted Gnas locus and its protein variants Galpha(s) and XLalpha(s) in human and mouse. J Endocrinol. 2008;196:193–214.

    CAS  PubMed  Google Scholar 

  13. Hayward BE, Kamiya M, Strain L, et al. The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc Natl Acad Sci U S A. 1998;95:10038–43.

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Hayward BE, Moran V, Strain L, et al. Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proc Natl Acad Sci U S A. 1998;95:15475–80.

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Yu S, Yu D, Lee E, Eckhaus M, et al. 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 U S A. 1998;95:8715–20.

    PubMed Central  CAS  PubMed  Google Scholar 

  16. Williamson CM, Ball ST, Nottingham WT, et al. A cis-acting control region is required exclusively for the tissue-specific imprinting of Gnas. Nat Genet. 2004;36:894–9.

    CAS  PubMed  Google Scholar 

  17. Mantovani G, Ballare E, Giammona E, et al. The Gsalpha gene: predominant maternal origin of transcription in human thyroid gland and gonads. J Clin Endocrinol Metab. 2002;87:4736–40.

    CAS  PubMed  Google Scholar 

  18. Germain-Lee EL, Ding CL, Deng Z, et al. Paternal imprinting of Galpha(s) in the human thyroid as the basis of TSH resistance in pseudohypoparathyroidism type 1a. Biochem Biophys Res Commun. 2002;296:67–72.

    CAS  PubMed  Google Scholar 

  19. Liu J, Erlichman B, Weinstein LS. The stimulatory G protein alpha-subunit Gs alpha is imprinted in human thyroid glands: Implications for thyroid function in pseudohypoparathyroidism types 1A and 1B. J Clin Endocrinol Metabol. 2003;88:4336–41.

    CAS  Google Scholar 

  20. Chen M, Wang J, Dickerson KE, et al. Central nervous system imprinting of the G protein G(s)alpha and its role in metabolic regulation. Cell Metab. 2009;9:548–55.

    PubMed Central  PubMed  Google Scholar 

  21. Hayward B, Barlier A, Korbonits M, et al. Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly. J Clin Invest. 2001;107:R31–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Cabrera-Vera TM, Vanhauwe J, Thomas TO, et al. Insights into G protein structure, function, and regulation. Endocr Rev. 2003;24:765–81.

    CAS  PubMed  Google Scholar 

  23. Marrari Y, Crouthamel M, Irannejad R, et al. Assembly and trafficking of heterotrimeric G proteins. Biochemistry. 2007;46:7665–77.

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Albright F, Burnett CH, Smith PH, et al. Pseudohypoparathyroidism—an example of ‘Seabright-Bantam syndrome’. Endocrinology. 1942;30:922–32.

    CAS  Google Scholar 

  25. Chase LR, Melson GL, Aurbach GD. Pseudohypoparathyroidism: defective excretion of 3’,5’-AMP in response to parathyroid hormone. J Clin Invest. 1969;48:1832–44.

    PubMed Central  CAS  PubMed  Google Scholar 

  26. Drezner M, Neelon FA, Lebovitz HE. Pseudohypoparathyroidism type II: a possible defect in the reception of the cyclic AMP signal. N Engl J Med. 1973;289:1056–60.

    CAS  PubMed  Google Scholar 

  27. Levine MA. Pseudohypoparathyroidism. In: Bilezikian JP, Raisz LG, Rodan GA, editors. Principles of bone biology. New York: Academic; 2002. p. 1137–63.

    Google Scholar 

  28. Weinstein LS, Yu S, Warner DR, et al. Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr Rev. 2001;22:675–705.

    CAS  PubMed  Google Scholar 

  29. Gelfand IM, Eugster EA, DiMeglio LA. Presentation and clinical progression of pseudohypoparathyroidism with multi-hormone resistance and Albright hereditary osteodystrophy: a case series. J Pediatr. 2006;149:877–80.

    PubMed  Google Scholar 

  30. Albright F, Forbes AP, Henneman PH. Pseudo-pseudohypoparathyroidism. Trans Assoc Am Physicians. 1952;65:337–50.

    CAS  PubMed  Google Scholar 

  31. Davies AJ, Hughes HE. Imprinting in Albright’s hereditary osteodystrophy. J Med Genet. 1993;30:101–3.

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Wilson LC, Oude-Luttikhuis MEM, Clayton PT, et al. Parental origin of Gsα gene mutations in Albright’s hereditary osteodystrophy. J Med Genet. 1994;31:835–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Moses AM, Weinstock RS, Levine MA, et al. Evidence for normal antidiuretic responses to endogenous and exogenous arginine vasopressin in patients with guanine nucleotide- binding stimulatory protein-deficient pseudohypoparathyroidism. J Clin Endocrinol Metab. 1986;62:221–4.

    CAS  PubMed  Google Scholar 

  34. Turan S, Thiele S, Tafaj O, et al. Evidence of hormone resistance in a pseudo-pseudohypoparathyroidism patient with a novel paternal mutation in GNAS . Bone. 02/2015; 71. doi: 10.1016/j.bone.2014.10.006.

  35. Lau K, Willig RP, Hiort O, et al. Linear skin atrophy preceding calcinosis cutis in pseudo-pseudohypoparathyroidism. Clin Exp Dermatol. 2012;37:646–8.

    CAS  PubMed  Google Scholar 

  36. Lebrun M, Richard N, Abeguilé G, et al. Progressive osseous heteroplasia: a model for the imprinting effects of GNAS inactivating mutations in humans. J Clin Endocrinol Metab. 2010;95:3028–38.

    CAS  PubMed  Google Scholar 

  37. Schuster V, Kress W, Kruse K. Paternal and maternal transmission of pseudohypoparathyroidism type Ia in a family with Albright hereditary osteodystrophy: no evidence of genomic imprinting. J Med Genet. 1994;31:84.

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Aldred MA, Aftimos S, Hall C, et al. Constitutional deletion of chromosome 20q in two patients affected with Albright hereditary osteodystrophy. Am J Med Genet. 2002;113:167–72.

    PubMed  Google Scholar 

  39. Ward S, Sugo E, Verge CF, et al. Three cases of osteoma cutis occurring in infancy. A brief overview of osteoma cutis and its association with pseudo-pseudohypoparathyroidism. Australas J Dermatol. 2011;52:127–31.

    PubMed  Google Scholar 

  40. Turan S, Fernandez-Rebollo E, Aydin C, et al. Postnatal establishment of allelic Gαs silencing as a plausible explanation for delayed onset of parathyroid hormone resistance owing to heterozygous Gαs disruption. J Bone Miner Res. 2014;29:749–60. In this experimental mice study, the authors showed that Gsα silencing in proximal renal tubule is established gradually after birth, and that PTH resistance in pseudohypoparathyroidism type-Ia develops mostly after infancy.

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Mantovani G, Bondioni S, Locatelli M, et al. Biallelic expression of the Gsalpha gene in human bone and adipose tissue. J Clin Endocrinol Metab. 2004;89:6316–19.

    CAS  PubMed  Google Scholar 

  42. Bastepe M, Weinstein LS, Ogata N, et al. Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Proc Natl Acad Sci U S A. 2004;101:14794–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Mouallem M, Shaharabany M, Weintrob N, et al. Cognitive impairment is prevalent in pseudohypoparathyroidism type Ia, but not in pseudopseudohypoparathyroidism: possible cerebral imprinting of Gsalpha. Clin Endocrinol (Oxf). 2008;68:233–9.

    CAS  Google Scholar 

  44. Long DN, McGuire S, Levine MA, et al. Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity. J Clin Endocrinol Metab. 2007;92:1073–9.

    CAS  PubMed  Google Scholar 

  45. Richard N, Molin A, Coudray N, et al. Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLαs in fetal development. J Clin Endocrinol Metab. 2013;98:E1549–56. This paper showed that paternal GNAS mutations cause intra uterine growth retardation and that this phenotype is likely related to the deficiency of the paternally expressed GNAS product XLαs.

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Plagge A, Gordon E, Dean W, et al. The imprinted signaling protein XL alpha s is required for postnatal adaptation to feeding. Nat Genet. 2004;36:818–26.

    CAS  PubMed  Google Scholar 

  47. Xie T, Plagge A, Gavrilova O, et al. The alternative stimulatory G protein alpha-subunit XLalphas is a critical regulator of energy and glucose metabolism and sympathetic nerve activity in adult mice. 2006;281:18989–99.

  48. Brix B, Werner R, Staedt P, et al. Different pattern of epigenetic changes of the GNAS gene locus in patients with pseudohypoparathyroidism type Ic confirm the heterogeneity of underlying pathomechanisms in this subgroup of pseudohypoparathyroidism and the demand for a new classification of GNAS-related disorders. J Clin Endocrinol Metab. 2014;99:E1564–70.

    CAS  PubMed  Google Scholar 

  49. Levine MA, Eil C, Downs Jr RW, et al. Deficient guanine nucleotide regulatory unit activity in cultured fibroblast membranes from patients with pseudohypoparathyroidism type I. a cause of impaired synthesis of 3',5'-cyclic AMP by intact and broken cells. J Clin Invest. 1983;72:316–24.

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Farfel Z, Brickman AS, Kaslow HR, et al. Defect of receptor-cyclase coupling protein in pseudohypoparathyroidism. N Engl J Med. 1980;303:237–42.

    CAS  PubMed  Google Scholar 

  51. Freson K, Izzi B, Jaeken J, et al. Compound heterozygous mutations in the GNAS gene of a boy with morbid obesity, thyroid-stimulating hormone resistance, pseudohypoparathyroidism, and a prothrombotic state. J Clin Endocrinol Metab. 2008;93:4844–9.

    CAS  PubMed  Google Scholar 

  52. Germain-Lee EL, Schwindinger W, Crane JL, Zewdu R, Zweifel LS, Wand G, et al. A mouse model of Albright hereditary osteodystrophy generated by targeted disruption of Exon 1 of the Gnas Gene. Endocrinology. 2005;146:4697–709.

    CAS  PubMed  Google Scholar 

  53. Chen M, Gavrilova O, Liu J, Xie T, Deng C, Nguyen AT, et al. Alternative Gnas gene products have opposite effects on glucose and lipid metabolism. Proc Natl Acad Sci U S A. 2005;102:7386–91.

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Linglart A, Carel JC, Garabedian M, et al. GNAS1 Lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance. J Clin Endocrinol Metab. 2002;87:189–97.

    CAS  PubMed  Google Scholar 

  55. Thiele S, de Sanctis L, Werner R, et al. Functional characterization of GNAS mutations found in patients with pseudohypoparathyroidism type Ic defines a new subgroup of pseudohypoparathyroidism affecting selectively Gsα-receptor interaction. Hum Mutat. 2011;32:653–60.

    PubMed Central  CAS  PubMed  Google Scholar 

  56. Iiri T, Herzmark P, Nakamoto JM, et al. Rapid GDP release from Gs alpha in patients with gain and loss of endocrine function. Nature. 1994;371:164–8.

    CAS  PubMed  Google Scholar 

  57. Nakamoto JM, Zimmerman D, Jones EA, et al. Concurrent hormone resistance (pseudohypoparathyroidism type Ia) and hormone independence (testotoxicosis) caused by a unique mutation in the G alpha s gene. Biochem Mol Med. 1996;58:18–24.

    CAS  PubMed  Google Scholar 

  58. Makita N, Sato J, Rondard P, et al. Human G(salpha) mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle. Proc Natl Acad Sci U S A. 2007;104:17424–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  59. Kaplan FS, Craver R, MacEwen GD, et al. Progressive osseous heteroplasia: a distinct developmental disorder of heterotopic ossification. Two new case reports and follow-up of three previously reported Cases. J Bone Joint Surg Am. 1994;76:425–36.

    CAS  PubMed  Google Scholar 

  60. Shore EM, Ahn J, Jan de Beur S, et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med. 2002;346:99–106.

    CAS  PubMed  Google Scholar 

  61. Cairns DM, Pignolo RJ, Uchimura T, et al. Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia. J Clin Invest. 2013;123:3624–33. The data from this study implicated that severe disruption of Gsα leads to progressive osseous heteroplasia (POH) and that somatic second hit mutations in addition to germline GNAS mutations could lead to POH, thus explaining the phenotypic heterogeneity of heterozygous GNAS mutations.

    PubMed Central  CAS  PubMed  Google Scholar 

  62. Regard JB, Malhotra D, Gvozdenovic-Jeremic J, et al. Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification. Nat Med. 2013;19:1505–12. In this paper, it was shown that Hedgehog signaling is upregulated in progressive osseous heteroplasia, which is a result of Gsα deficiency caused by inactivating GNAS mutations. Additionally, genetically-mediated ectopic Hedgehog signaling is sufficient to induce heterotopic ossification in animal models, and the genetic or pharmacological inhibition of this signaling pathway reduces the severity of ectopic ossification.

    PubMed Central  CAS  PubMed  Google Scholar 

  63. Liu J, Litman D, Rosenberg MJ, et al. A GNAS1 imprinting defect in pseudohypoparathyroidism type IB. J Clin Invest. 2000;106:1167–74.

    PubMed Central  CAS  PubMed  Google Scholar 

  64. Bastepe M, Pincus JE, Sugimoto T, et al. 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. 2001;10:1231–41.

    CAS  PubMed  Google Scholar 

  65. de Nanclares GP, Fernández-Rebollo E, Santin I, et al. Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright's hereditary osteodystrophy. J Clin Endocrinol Metab. 2007;92:2370–3.

    PubMed  Google Scholar 

  66. Mariot V, Maupetit-Mehouas S, Sinding C, et al. A maternal epimutation of GNAS leads to Albright osteodys-trophy and parathyroid hormone resistance. J Clin Endocrinol Metab. 2008;93:661–5.

    CAS  PubMed  Google Scholar 

  67. Unluturk U, Harmanci A, Babaoglu M, et al. Molecular diagnosis and clinical characterization of pseudohypoparathyroidism type-Ib in a patient with mild Albright’s hereditary osteodystrophy-like features, epileptic seizures, and defective renal handling of uric acid. Am J Med Sci. 2008;336:84–90.

    PubMed  Google Scholar 

  68. Mantovani G, de Sanctis L, Barbieri AM, et al. Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of Albright hereditary osteodystrophy and molecular analysis in 40 patients. J Clin Endocrinol Metab. 2010;95:651–8.

    CAS  PubMed  Google Scholar 

  69. Sanchez J, Perera E, Jan de Beur S, et al. Madelung-like deformity in pseudohypoparathyroidism type 1b. J Clin Endocrinol Metab. 2011;96:E1507–11.

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Zazo C, Thiele S, Martín C, et al. Gsα activity is reduced in erythrocyte membranes of patients with pseudohypoparathyroidism due to epigenetic alterations at the GNAS locus. J Bone Miner Res. 2011;26:1864–70.

    CAS  PubMed  Google Scholar 

  71. Jüppner H, Schipani E, Bastepe M, et al. 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. 1998;95:11798–803.

    PubMed Central  PubMed  Google Scholar 

  72. Bastepe M, Fröhlich LF, Hendy GN, et al. Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. J Clin Invest. 2003;112:1255–63.

    PubMed Central  CAS  PubMed  Google Scholar 

  73. Linglart A, Gensure RC, Olney RC, et al. 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. 2005;76:804–14.

    PubMed Central  CAS  PubMed  Google Scholar 

  74. Elli FM, de Sanctis L, Peverelli E, et al. Autosomal dominant pseudohypoparathyroidism type Ib: a novel inherited deletion ablating STX16 causes loss of imprinting at the A/B DMR. J Clin Endocrinol Metab. 2014;99:E724–8.

    CAS  PubMed  Google Scholar 

  75. Richard N, Abeguilé G, Coudray N, et al. A new deletion ablating NESP55 causes loss of maternal imprint of A/B GNAS and autosomal dominant pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab. 2012;97:E863–7. A novel deletion of 18,988 bp that removes NESP55 and a large upstream intronic region was discovered in a familial case with PHP-Ib in which maternal transmission causes loss of A/B methylation without affecting XL/AS imprinting; paternal transmission of the same deletion leads to no methylation anomalies. Taken together with the previously reported deletions, these findings indicate that isolated loss of A/B methylation can be caused by distinct, non-overlapping deletions in the STX16-GNAS region.

    CAS  PubMed  Google Scholar 

  76. Tang BL, Low DY, Lee SS, et al. Molecular cloning and localization of human syntaxin 16, a member of the syntaxin family of SNARE proteins. Biochem Biophys Res Commun. 1998;242:673–9.

    CAS  PubMed  Google Scholar 

  77. Fröhlich LF, Bastepe M, Ozturk D, et al. Lack of Gnas epigenetic changes and pseudohypoparathyroidism type Ib in mice with targeted disruption of syntaxin-16. Endocrinology. 2007;148:2925–35.

    PubMed  Google Scholar 

  78. Bastepe M, Fröhlich LF, Linglart A, et al. Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nat Genet. 2005;37:25–7.

    CAS  PubMed  Google Scholar 

  79. Chillambhi S, Turan S, Hwang DY, et al. Deletion of the noncoding GNAS antisense transcript causes pseudohypoparathyroidism type Ib and biparental defects of GNAS methylation in cis. J Clin Endocrinol Metab. 2010;95:3993–4002.

    PubMed Central  CAS  PubMed  Google Scholar 

  80. Fröhlich LF, Mrakovcic M, Steinborn R, et al. 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. 2010;107:9275–80.

    PubMed Central  PubMed  Google Scholar 

  81. Fernández-Rebollo E, Maeda A, Reyes M, et al. Loss of XLαs (extra-large αs) imprinting results in early postnatal hypoglycemia and lethality in a mouse model of pseudohypoparathyroidism Ib. Proc Natl Acad Sci U S A. 2012;109:6638–43. By showing improved survival upon normalization of XLαs expression, this study proved that the biallelic expression of XLαs is responsible for the early postnatal lethality in mice with deletion of the Nesp55 DMR. Surviving double-mutant animals had significantly reduced Gsα mRNA levels and showed hypocalcemia, hyperphosphatemia, and elevated PTH levels, thus providing a viable model of human AD-PHP-Ib.

    PubMed Central  PubMed  Google Scholar 

  82. Chotalia M, Smallwood SA, Ruf N, et al. Transcription is required for establishment of germline methylation marks at imprinted genes. Genes Dev. 2009;23:105–17.

    PubMed Central  CAS  PubMed  Google Scholar 

  83. Williamson CM, Turner MD, Ball ST, et al. Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster. Nat Genet. 2006;38:350–5.

    CAS  PubMed  Google Scholar 

  84. Eaton SA, Williamson CM, Ball ST, et al. New mutations at the imprinted Gnas cluster show gene dosage effects of Gsα in postnatal growth and implicate XLαs in bone and fat metabolism but not in suckling. Mol Cell Biol. 2012;32:1017–29. This paper showed that the loss of ALEX is most likely responsible for the suckling defects in XLαs knockout pups. Additionally, increased metabolic rate and reductions in fat mass, leptin, and bone mineral density were attributed to the loss of XLαs. Moreover, the authors terminated the A/B transcript prematurely and thereby provided evidence that the tissue-specific paternal Gsα silencing results from transcriptional interference from the upstream A/B transcript.

    PubMed Central  CAS  PubMed  Google Scholar 

  85. Liu J, Nealon JG, Weinstein LS. Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB. Hum Mol Genet. 2005;14:95–102.

    CAS  PubMed  Google Scholar 

  86. Linglart A, Bastepe M, Jüppner H. 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). 2007;67(6):822–31.

    CAS  Google Scholar 

  87. Fernández-Rebollo E, Pérez de Nanclares G, Lecumberri B, et al. Exclusion of the GNAS locus in PHP-Ib patients with broad GNAS methylation changes: evidence for an autosomal recessive form of PHP-Ib? J Bone Miner Res. 2011;26:1854–63.

    PubMed  Google Scholar 

  88. Bastepe M, Lane AH, Jüppner H. Paternal uniparental isodisomy of chromosome 20q—and the resulting changes in GNAS1 methylation—as a plausible cause of pseudohypoparathyroidism. Am J Hum Genet. 2001;68:1283–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  89. Bastepe M, Altug-Teber O, Agarwal C, et al. Paternal uniparental isodisomy of the entire chromosome 20 as a molecular cause of pseudohypoparathyroidism type Ib (PHP-Ib). Bone. 2011;48:659–62.

    PubMed Central  CAS  PubMed  Google Scholar 

  90. Fernández-Rebollo E, Lecumberri B, Garin I, et al. New mechanisms involved in paternal 20q disomy associated with pseudohypoparathyroidism. Eur J Endocrinol. 2010;163:953–62.

    PubMed  Google Scholar 

  91. Dixit A, Chandler KE, Lever M, et al. Pseudohypoparathyroidism type 1b due to paternal uniparental disomy of chromosome 20q. J Clin Endocrinol Metab. 2013;98:E103–8.

    CAS  PubMed  Google Scholar 

  92. Lecumberri B, Fernández-Rebollo E, Sentchordi L, et al. Coexistence of two different pseudohypoparathyroidism subtypes (Ia and Ib) in the same kindred with independent Gs{alpha} coding mutations and GNAS imprinting defects. J Med Genet. 2010;47:276–80.

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Cavaco BM, Tomaz RA, Fonseca F, et al. Clinical and genetic characterization of Portuguese patients with pseudohypoparathyroidism type Ib. Endocrine. 2010;37:408–14.

    CAS  PubMed  Google Scholar 

  94. Rezwan FI, Poole RL, Prescott T, et al. Very small deletions within the NESP55 gene in pseudohypoparathyroidism type 1b. Eur J Hum Genet. 2014. doi:10.1038/ejhg.2014.

    PubMed  Google Scholar 

  95. Vermeiden JP, Bernardus RE. Are imprinting disorders more prevalent after human in vitro fertilization or intracytoplasmic sperm injection? Fertil Steril. 2013;99:642–51.

    PubMed  Google Scholar 

  96. DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet. 2003;72:156–60.

    PubMed Central  CAS  PubMed  Google Scholar 

  97. Bliek J, Verde G, Callaway J, et al. Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2009;17:611–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Mackay DJ, Callaway JL, Marks SM, et al. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet. 2008;40:949–51.

    CAS  PubMed  Google Scholar 

  99. Perez-Nanclares G, Romanelli V, Mayo S, et al. Spanish PHP Group: detection of hypomethylation syndrome among patients with epigenetic alterations at the GNAS locus. J Clin Endocrinol Metab. 2012;97:E1060–7. The authors found that multilocus imprinting defects, which has been described in some growth disorders, was rarely present in patients with pseudohypoparathyroidism Ib who had broad GNAS methylation defects and lacked any of the previously described microdeletions or paternal uniparental disomy of chromosome 20.

    CAS  PubMed  Google Scholar 

  100. Lefebvre L, Viville S, Barton SC, et al. Abnormal maternal behaviour and growth retardation associated with loss of the imprinted gene Mest. Nat Genet. 1998;20:163–9.

    CAS  PubMed  Google Scholar 

  101. Landis CA, Masters SB, Spada A, et al. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature. 1989;34:692–6.

    Google Scholar 

  102. Weinstein LS, Shenker A, Gejman PV, et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med. 1991;325:1688–95.

    CAS  PubMed  Google Scholar 

  103. Bianco P, Riminucci M, Majolagbe A, et al. Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCune-Albright fibrous dysplasia of bone. J Bone Miner Res. 2000;15:120–8.

    CAS  PubMed  Google Scholar 

  104. Idowu BD, Al-Adnani M, O'Donnell P, et al. A sensitive mutation-specific screening technique for GNAS1 mutations in cases of fibrous dysplasia: the first report of a codon 227 mutation in bone. Histopathology. 2007;50:691–704.

    CAS  PubMed  Google Scholar 

  105. Happle R. The McCune-Albright syndrome: a lethal gene surviving by mosaicism. Clin Genet. 1986;29:321–4.

    CAS  PubMed  Google Scholar 

  106. Saggio I, Remoli C, Spica E, et al. Constitutive expression of Gsα(R201C) in mice produces a heritable, direct replica of human fibrous dysplasia bone pathology and demonstrates its natural history. J Bone Miner Res. 2014;29:2357–68.

    CAS  PubMed  Google Scholar 

  107. McCune DJ. Osteitis fibrosa cystica: the case of a nine-year-old girl who also exhibits precocious puberty, multiple pigmentation of the skin and hyperthyroidism. Am J Dis Child. 1936;52:743–4.

    Google Scholar 

  108. Albright F, Butler AM, Hampton AO, et al. Syndrome characterized by osteitis fibrosa disseminata, areas, of pigmentation, and endocrine dysfunction, with precocious puberty in females: report of 5 cases. N Engl J Med. 1937;216:727–46.

    Google Scholar 

  109. Spiegel AM, Weinstein LS. Inherited diseases involving g proteins and g protein-coupled receptors. Annu Rev Med. 2004;55:27–39.

    CAS  PubMed  Google Scholar 

  110. Collins MT, Singer FR, Eugster E. McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia. Orphanet J Rare Dis. 2012;7 Suppl 1:S4.

    PubMed Central  PubMed  Google Scholar 

  111. Lichtenstein LJH. Fibrous dysplasia of bone: a condition affecting one, several or many bones, graver cases of which may present abnormal pigmentation of skin, premature sexual development, hyperthyroidism or still other extraskeletal abnormalities. Arch Path. 1942;33:777–816.

    Google Scholar 

  112. Bianco P, Robey PG, Wientroub S. Fibrous dysplasia. In: Glorieux FH, Pettifor J, Juppner H, editors. Pediatric bone: biology and disease. New York: Academic, Elsevier; 2003. p. 509–39.

    Google Scholar 

  113. Collins MT. Spectrum and natural history of fibrous dysplasia of bone. J Bone Miner Res. 2006;21 Suppl 2:99–P104.

    Google Scholar 

  114. Wu JY, Aarnisalo P, Bastepe M, et al. Gsα enhances commitment of mesenchymal progenitors to the osteoblast lineage but restrains osteoblast differentiation in mice. J Clin Invest. 2011;121:3492–504. The conditional Gsα knock-out in osterix-expressing cells led to severe osteoporosis with fractures at birth, as a consequence of impaired bone formation related to rapid differentiation of mature osteoblasts leading to decreased osteoblast pool, rather than increased resorption. This study thus demonstrated the critical role of Gsα in temporal regulation of osteogenesis.

    PubMed Central  CAS  PubMed  Google Scholar 

  115. Riminucci M, Fisher LW, Shenker A, et al. Fibrous dysplasia of bone in the McCune-Albright syndrome: abnormalities in bone formation. Am J Pathol. 1997;151:1587–600.

    PubMed Central  CAS  PubMed  Google Scholar 

  116. Marie PJ, de Pollak C, Chanson P, et al. Increased proliferation of osteoblastic cells expressing the activating Gs alpha mutation in monostotic and polyostotic fibrous dysplasia. Am J Pathol. 1997;150:1059–69.

    PubMed Central  CAS  PubMed  Google Scholar 

  117. Cone RD, Lu D, Koppula S, et al. The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog Horm Res. 1996;51:287–317.

    CAS  PubMed  Google Scholar 

  118. Riminucci M, Collins MT, Fedarko NS, et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest. 2003;112:683–92.

    PubMed Central  CAS  PubMed  Google Scholar 

  119. Collins MT, Chebli C, Jones J, et al. Renal phosphate wasting in fibrous dysplasia of bone is part of a generalized renal tubular dysfunction similar to that seen in tumor-induced osteomalacia. J Bone Miner Res. 2001;16:806–13.

    CAS  PubMed  Google Scholar 

  120. Bhattacharyya N, Wiench M, Dumitrescu C, et al. Mechanism of FGF23 processing in fibrous dysplasia. J Bone Miner Res. 2012;27:1132–41.

    CAS  PubMed  Google Scholar 

  121. Rhee Y, Bivi N, Farrow E, et al. Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone. 2011;49:636–43.

    PubMed Central  CAS  PubMed  Google Scholar 

  122. Lavi-Moshayoff V, Wasserman G, Meir T, et al. PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Renal Physiol. 2010;299:F882–9.

    CAS  PubMed  Google Scholar 

  123. Mantovani G, Bondioni S, Lania AG, et al. Parental origin of Gsalpha mutations in the McCune-Albright syndrome and in isolated endocrine tumors. J Clin Endocrinol Metab. 2004;89:3007–9.

    CAS  PubMed  Google Scholar 

  124. Mariot V, Wu JY, Aydin C, et al. Potent constitutive cyclic AMP-generating activity of XLαs implicates this imprinted GNAS product in the pathogenesis of McCune-Albright syndrome and fibrous dysplasia of bone. Bone. 2011;48:312–20.

    PubMed Central  CAS  PubMed  Google Scholar 

  125. Lyons J, Landis CA, Harsh G, et al. Two G protein oncogenes in human endocrine tumors. Science. 1990;249:655–9.

    CAS  PubMed  Google Scholar 

  126. Yoshimoto K, Iwahana H, Fukuda A, et al. Rare mutations of the Gs alpha subunit gene in human endocrine tumors. Mutation detection by polymerase chain reaction-primer-introduced restriction analysis. Cancer. 1993;72:1386–93.

    CAS  PubMed  Google Scholar 

  127. Nault JC, Fabre M, Couchy G, et al. GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation. J Hepatol. 2012;56:184–91.

    CAS  PubMed  Google Scholar 

  128. Kalfa N, Lumbroso S, Boulle N, et al. Activating mutations of Gsalpha in kidney cancer. J Urol. 2006;176:891–5.

    CAS  PubMed  Google Scholar 

  129. Wu J, Matthaei H, Maitra A, et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med. 2011;3:92ra66. The authors found that GNAS mutations were present in 66% of intraductal papillary mucinous neoplasms (IPMN), one of the most common cystic neoplasms of the pancreas and a precursor to invasive adenocarcinoma. 96% of IPMN have either KRAS or GNAS mutations. This new finding could be a new hope for the management of pancreatic carcinoma.

    PubMed Central  CAS  PubMed  Google Scholar 

  130. Fecteau RE, Lutterbaugh J, Markowitz SD, et al. GNAS mutations identify a set of right-sided, RAS mutant, villous colon cancers. PLoS One. 2014;9:e87966.

    PubMed Central  PubMed  Google Scholar 

  131. Liu Z, Turan S, Wehbi VL, et al. Extra-long Gαs variant XLαs protein escapes activation-induced subcellular redistribution and is able to provide sustained signaling. J Biol Chem. 2011;286:38558–69.

    PubMed Central  CAS  PubMed  Google Scholar 

  132. Garcia-Murillas I, Sharpe R, Pearson A, et al. An siRNA screen identifies the GNAS locus as a driver in 20q amplified breast cancer. Oncogene. 2014;33:2478–86.

    PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The studies conducted in the laboratory of M.B. are funded in part by research grants from the National Institute of Diabetes and Digestive and Kidney Diseases (RO1 DK073911), the March of Dimes Foundation, and the Milton Fund.

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

S Turan and M Bastepe both declare no conflicts of interest.

Human and Animal Rights and Informed Consent

All studies by the authors involving animal and/or human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.

Author information

Authors and Affiliations

  1. Pediatric Endocrinology, Marmara University School of Medicine Hospital, Istanbul, Turkey

    Serap Turan

  2. Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, 55 Fruit St. Thier 10, Boston, MA, 02114, USA

    Murat Bastepe

Authors
  1. Serap Turan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Murat Bastepe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Murat Bastepe.

Additional information

This article is part of the Topical Collection on Rare Bone Disease

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Turan, S., Bastepe, M. GNAS Spectrum of Disorders. Curr Osteoporos Rep 13, 146–158 (2015). https://doi.org/10.1007/s11914-015-0268-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-015-0268-x

Keywords

Search

Navigation