The GNAS Locus and Pseudohypoparathyroidism

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 626)

Abstract

Pseudohypoparathyroidism (PHP) is a disorder of end-organ resistance primarily affecting the actions of parathyroid hormone (PTH). Genetic defects associated with different forms of PHP involve the α-subunit of the stimulatory G protein (Gsα), a signaling protein essential for the actions of PTH and many other hormones. Heterozygous inactivating mutations within Gsα-encoding GNAS exons are found in patients with PHP-Ia, who also show resistance to other hormones and a constellation of physical features called Albright’s hereditary osteodystrophy (AHO). Patients who exhibit AHO features without evidence for hormone resistance, who are said to have pseudopseudohypoparathyroidism (PPHP), also carry heterozygous inactivating Gsα mutations. Maternal inheritance of such a mutation leads to PHP-Ia, i.e., AHO plus hormone resistance, while paternal inheritance of the same mutation leads to PPHP, i.e., AHO only. This imprinted mode of inheritance for hormone resistance can be explained by the predominantly maternal expression of Gsα in certain tissues, including renal proximal tubules. Patients with PHP-Ib lack coding Gsα mutations but display epigenetic defects of the GNAS locus, with the most consistent defect being a loss of imprinting at the exon A/B differentially methylated region (DMR). This epigenetic defect presumably silences, in cis, Gsα expression in tissues where this protein is derived from the maternal allele only, leading to a marked reduction of Gsα levels. The familial form of PHP-Ib (AD-PHP-Ib) is typically associated with an isolated loss of imprinting at the exon A/B DMR. A unique 3-kb microdeletion that disrupts the neighboring STX16 locus has been identified in this disorder and appears to be the cause of the loss of imprinting. In addition, deletions removing the entire NESP55 DMR, located within GNAS, have been identified in some AD-PHP-Ib kindreds in whom affected individuals show loss of all the maternal GNAS imprints. Mutations identified in different forms of PHP-Ib thus point to different cis-acting elements that are apparently required for the proper imprinting of the GNAS locus. Most sporadic PHP-Ib cases also have imprinting abnormalities of GNAS that involve multiple DMRs, but the genetic lesion(s) responsible for these imprinting abnormalities remain to be discovered.

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References

  1. 1.
    Yu S, Yu D, Lee E et al. 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 USA 1998; 95:8715–8720.PubMedCrossRefGoogle Scholar
  2. 2.
    Chen M, Gavrilova O, Liu J et al. Alternative Gnas gene products have opposite effects on glucose and lipid metabolism. Proc Natl Acad Sci USA 2005; 102(20):7386–7391.PubMedCrossRefGoogle Scholar
  3. 3.
    Germain-Lee EL, Schwindinger W, Crane JL et al. A Mouse Model of Albright Hereditary Osteodystrophy Generated by Targeted Disruption of Exon 1 of the Gnas Gene. Endocrinology 2005; 146(11):4697–4709.PubMedCrossRefGoogle Scholar
  4. 4.
    Spiegel AM, Weinstein LS. Inherited diseases involving g proteins and g protein-coupled receptors. Annu Rev Med 2004; 55:27–39.PubMedCrossRefGoogle Scholar
  5. 5.
    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(5):675–705.PubMedCrossRefGoogle Scholar
  6. 6.
    Potts JT. Parathyroid hormone: past and present. J Endocrinol 2005; 187(3):311–325.PubMedCrossRefGoogle Scholar
  7. 7.
    Gensure RC, Gardella TJ, Jüppner H. Parathyroid hormone and parathyroid hormone-related peptide and their receptors. Biochem Biophys Res Commun 2005; 328(3):666–678.PubMedCrossRefGoogle Scholar
  8. 8.
    Ish-Shalom S, Rao LG, Levine MA et al. Normal parathyroid hormone responsiveness of bone-derived cells from a patient with pseudo hypoparathyroidism. J Bone Miner Res 1996; 11:8–14.PubMedGoogle Scholar
  9. 9.
    Murray T, Gomez Rao E, Wong MM et al. Pseudohypoparathyroidism with osteitis fibrosa cystica: direct demonstration of skeletal responsiveness to parathyroid hormone in cells cultured from bone. J Bone Miner Res 1993; 8:83–91.PubMedCrossRefGoogle Scholar
  10. 10.
    Stone M, Hosking D, Garcia-Himmelstine C et al. The renal response to exogenous parathyroid hormone in treated pseudohypoparathyroidism. Bone 1993; 14:727–735.PubMedCrossRefGoogle Scholar
  11. 11.
    Breslau NA, Weinstock RS. Regulation of 1,25(OH)2D synthesis in hypoparathyroidism and pseudohypoparathyroidism. Am J Physiol 1988; 255:E730–E736.PubMedGoogle Scholar
  12. 12.
    Drezner MK, Neelon FA, Haussler M et al. 1,25-dihydroxycholecalciferol deficiency: the probable cause of hypocalcemia and metabolic bone disease in pseudohypoparathyroidism. J Clin Endocrinol Metab 1976; 42:621–628.PubMedCrossRefGoogle Scholar
  13. 13.
    Chase LR, Melson GL, Aurbach GD. Pseudohypoparathyroidism: defective excretion of 3′,5′-AMP in response to parathyroid hormone. J Clin Invest 1969; 48:1832–1844.PubMedCrossRefGoogle Scholar
  14. 14.
    Albright F, Burnett CH, Smith PH et al. Pseudohypoparathyroidism—an example of “Seabright-Bantam syndrome”. Endocrinology 1942; 30:922–932.Google Scholar
  15. 15.
    Farfel Z. Pseudohypohyperparathyroidism-pseudohypoparathyroidism type Ib. J Bone Miner Res 1999; 14:1016.PubMedCrossRefGoogle Scholar
  16. 16.
    Bastepe M, Jüppner H. GNAS locus and pseudohypoparathyroidism. Horm Res 2005; 63(2):65–74.PubMedCrossRefGoogle Scholar
  17. 17.
    Levine MA, Downs RW Jr, Moses AM et al. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein. Am J Med 1983; 74:545–556.PubMedCrossRefGoogle Scholar
  18. 18.
    Mallet E, Carayon P, Amr S et al. Coupling defect of thyrotropin receptor and adenylate cyclase in a pseudohypoparathyroid patient. J Clin Endocrinol Metab 1982; 54(5):1028–1032.PubMedCrossRefGoogle Scholar
  19. 19.
    Wolfsdorf JI, Rosenfield RL, Fang VS et al. Partial gonadotrophin-resistance in pseudohypoparathyroidism. Acta Endocrinol (Copenh) 1978; 88(2):321–328.Google Scholar
  20. 20.
    Mantovani G, Maghnie M, Weber G et al. Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type ia: new evidence for imprinting of the Gs alpha gene. J Clin Endocrinol Metab 2003; 88(9):4070–4074.PubMedCrossRefGoogle Scholar
  21. 21.
    Germain-Lee EL, Groman J, Crane JL et al. Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J Clin Endocrinol Metab 2003; 88(9):4059–4069.PubMedCrossRefGoogle Scholar
  22. 22.
    Faull CM, Welbury RR, Paul B et al. Pseudohypoparathyroidism: its phenotypic variability and associated disorders in a large family. Q J Med 1991; 78(287):251–264.PubMedGoogle Scholar
  23. 23.
    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; 62:221–224.PubMedCrossRefGoogle Scholar
  24. 24.
    Tsai KS, Chang CC, Wu DJ et al. Deficient erythrocyte membrane Gs alpha activity and resistance to trophic hormones of multiple endocrine organs in two cases of pseudohypoparathyroidism. Taiwan Yi Xue Hui Za Zhi 1989; 88(5):450–455.PubMedGoogle Scholar
  25. 25.
    Weinstein LS, Gejman PV, Friedman E et al. Mutations of the Gs alpha-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc Natl Acad Sci USA 1990; 87(21):8287–8290.PubMedCrossRefGoogle Scholar
  26. 26.
    Patten JL, Johns DR, Valle D et al. Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright’s hereditary osteodystrophy. New Engl. J Med 1990; 322:1412–1419.PubMedCrossRefGoogle Scholar
  27. 27.
    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(2):167–172.PubMedCrossRefGoogle Scholar
  28. 28.
    Levine MA, Ahn TG, Klupt SF et al. Genetic deficiency of the alpha subunit of the guanine nucleotide-binding protein Gs as the molecular basis for Albright hereditary osteodystrophy. Proc Natl Acad Sci USA 1988; 85(2):617–621.PubMedCrossRefGoogle Scholar
  29. 29.
    Patten JL, Levine MA. Immunochemical analysis of the a-subunit of the stimulatory G-protein of adenylyl cyclase in patients with Albright’s hereditary osteodystrophy. J Clin Endocrinol Metab 1990; 71:1208–1214.PubMedCrossRefGoogle Scholar
  30. 30.
    Carter A, Bardin C, Collins R et al. Reduced expression of multiple forms of the a subunit of the stimulatory GTP-binding protein in pseudohypoparathyroidism type Ia. Proc Natl Acad Sci USA 1987; 84:7266–7269.PubMedCrossRefGoogle Scholar
  31. 31.
    Farfel Z, Brickman AS, Kaslow HR et al. Defect of receptor-cyclase coupling protein in pseudohypoparathyroidism. N Engl J Med 1980; 303:237–242.PubMedGoogle Scholar
  32. 32.
    Levine MA, Downs RW Jr, Singer M et al. Deficient activity of guanine nucleotide regulatory protein in erythrocytes from patients with pseudohypoparathyroidism. Biochem Biophys Res Commun 1980; 94:1319–1324.PubMedCrossRefGoogle Scholar
  33. 33.
    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(1):189–197.PubMedCrossRefGoogle Scholar
  34. 34.
    Linglart A, Mahon MJ, Kerachian MA et al. Coding GNAS mutations leading to hormone resistance impair in vitro agonist-and cholera toxin-induced cAMP formation mediated by human XL{alpha}s. Endocrinology 2006; 147(5):2253–62.PubMedCrossRefGoogle Scholar
  35. 35.
    Farfel Z, Brothers VM, Brickman AS et al. Pseudohypoparathyroidism: inheritance of deficient receptor-cyclase coupling activity. Proc Natl Acad Sci USA 1981; 78(5):3098–3102.PubMedCrossRefGoogle Scholar
  36. 36.
    Albright F, Forbes AP, Henneman PH. Pseudo-pseudohypoparathyroidism. Trans Assoc Am Physicians 1952; 65:337–350.PubMedGoogle Scholar
  37. 37.
    Levine MA, Jap TS, Mauseth RS et al. Activity of the stimulatory guanine nucleotide-binding protein is reduced in erythrocytes from patients with pseudohypoparathyroidism and pseudohypoparathyroidism: Biochemical, endocrine and genetic analysis of Albright’s hereditary osteodystrophy in six kindreds. J Clin Endocrinol Metab 1986; 62:497–502.PubMedCrossRefGoogle Scholar
  38. 38.
    Davies AJ, Hughes HE. Imprinting in Albright’s hereditary osteodystrophy. J Med Genet 1993; 30:101–103.PubMedCrossRefGoogle Scholar
  39. 39.
    Wilson LC, Oude-Luttikhuis MEM, Clayton PT et al. Parental origin of Gsa gene mutations in Albright’s hereditary osteodystrophy. J Med Genet 1994; 31:835–839.PubMedCrossRefGoogle Scholar
  40. 40.
    Kaplan FS, Shore EM. Progressive osseous heteroplasia. J Bone Miner Res 2000; 15(11):2084–2094.PubMedCrossRefGoogle Scholar
  41. 41.
    Eddy MC, De Beur SM, Yandow SM et al. Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification. J Bone Miner Res 2000; 15(11):2074–2083.PubMedCrossRefGoogle Scholar
  42. 42.
    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(2):99–106.PubMedCrossRefGoogle Scholar
  43. 43.
    Ahmed SF, Barr DG, Bonthron DT. GNAS1 mutations and progressive osseous heteroplasia. N Engl J Med 2002; 346(21):1669–1671.PubMedCrossRefGoogle Scholar
  44. 44.
    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 USA 2004; 101(41):14794–14799.PubMedCrossRefGoogle Scholar
  45. 45.
    Sakamoto A, Chen M, Kobayashi T et al. 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 2005; 20(4):663–671.PubMedCrossRefGoogle Scholar
  46. 46.
    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(10):4736–4740.PubMedCrossRefGoogle Scholar
  47. 47.
    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 Ia. Biochem Biophys Res Commun 2002; 296(1):67–72.PubMedCrossRefGoogle Scholar
  48. 48.
    Liu J, Erlichman B, Weinstein LS. 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 2003; 88(9):4336–4341.CrossRefGoogle Scholar
  49. 49.
    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:R31–36.PubMedCrossRefGoogle Scholar
  50. 50.
    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(12):6316–6319.PubMedCrossRefGoogle Scholar
  51. 51.
    Zheng R, Radeva G, McCann JA et al. Gas transcripts are biallelically expressed in the human kidney cortex: implications for pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab 2001; 86(10):4627–4629.PubMedCrossRefGoogle Scholar
  52. 52.
    Tsang R, Venkataraman P, Ho M et al. The development of pseudo hypoparathyroidism. Involvement of progressively increasing serum parathyroid hormone concentrations, increased 1,25-dihydroxyvitamin D concentrations and ‘migratory’ subcutaneous calcifications. Am J Dis Child 1984; 138:654–658.PubMedGoogle Scholar
  53. 53.
    Barr DG, Stirling HF, Darling JA. Evolution of pseudohypoparathyroidism: an informative family study. Arch Dis Child 1994; 70(4):337–338.PubMedCrossRefGoogle Scholar
  54. 54.
    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(5):804–814.PubMedCrossRefGoogle Scholar
  55. 55.
    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 USA 1998; 95:11798–11803.PubMedCrossRefGoogle Scholar
  56. 56.
    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; 10:1231–1241.PubMedCrossRefGoogle Scholar
  57. 57.
    Bastepe M, Lane AH, Jüppner H. Paternal uniparental isodisomy of chromosome 20q (patUPD20q)— and the resulting changes in GNAS1 methylation—as a plausible cause of pseudohypoparathyroidism. Am J Hum Genet 2001; 68:1283–1289.PubMedCrossRefGoogle Scholar
  58. 58.
    Silve C, Santora A, Breslau N et al. Selective resistance to parathyroid hormone in cultured skin fibroblasts from patients with pseudohypoparathyroidism type Ib. J Clin endocrinol Metab 1986; 62:640–644.PubMedCrossRefGoogle Scholar
  59. 59.
    Schipani E, Weinstein LS, Bergwitz C et al. Pseudohypoparathyroidism type Ib is not caused by mutations in the coding exons of the human parathyroid hormone (PTH)/PTH-related peptide receptor gene. J Clin Endocrinol Metab 1995; 80:1611–1621.PubMedCrossRefGoogle Scholar
  60. 60.
    Fukumoto S, Suzawa M, Takeuchi Y et al. Absence of mutations in parathyroid hormone (PTH)/PTH-related protein receptor complementary deoxyribonucleic acid in patients with pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab 1996; 81:2554–2558.PubMedCrossRefGoogle Scholar
  61. 61.
    Ding CL, Usdin TB, Labuda M et al. Molecular genetic analysis of pseudohypoparathyroidism type Ib: exclusion of the genes encoding the type 1 and type 2 PTH receptors. J Bone Miner Res 1996; 11(suppl 1):M483.Google Scholar
  62. 62.
    Bettoun JD, Minagawa M, Kwan MY et al. Cloning and characterization of the promoter regions of the human parathyroid hormone (PTH)/PTH-related peptide receptor gene: analysis of deoxyribonucleic acid from normal subjects and patients with pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab 1997; 82:1031–1040.PubMedCrossRefGoogle Scholar
  63. 63.
    Fukumoto S, Suzawa M, Kikuchi T et al. Cloning and characterization of kidney-specific promoter of human PTH/PTHrP receptor gene: absence of mutation in patients with pseudohypoparathyroidism type Ib. Mol Cell Endocrinol 1998; 141:41–47.PubMedCrossRefGoogle Scholar
  64. 64.
    Jan De Beur SM, O’Connell JR, Peila R et al. The pseudohypoparathyroidism type lb locus is linked to a region including GNAS1 at 20q13.3. J Bone Miner Res 2003; 18(3):424–433.PubMedCrossRefGoogle Scholar
  65. 65.
    Liu J, Litman D, Rosenberg M et al. A GNAS1 imprinting defect in pseudohypoparathyroidism type IB. J Clin Invest 2000; 106:1167–1174.PubMedCrossRefGoogle Scholar
  66. 66.
    Liu J, Yu S, Litman D et al. Identification of a methylation imprint mark within the mouse gnas locus. Mol Cell Biol 2000; 20:5808–5817.PubMedCrossRefGoogle Scholar
  67. 67.
    Swaroop A, Agarwal N, Gruen JR et al. Differential expression of novel Gs alpha signal transduction protein cDNA species. Nucleic Acids Res 1991; 19(17):4725–4729.PubMedCrossRefGoogle Scholar
  68. 68.
    Dou D, Joseph R. Cloning of human neuronatin gene and its localization to chromosome-20q 11.2-12: the deduced protein is a novel ‘proteolipid’. Brain Res 1996; 723(1–2):8–22.PubMedCrossRefGoogle Scholar
  69. 69.
    Kikyo N, Williamson CM, John RM et al. Genetic and functional analysis of neuronatin in mice with maternal or paternal duplication of distal Chr 2. Dev Biol 1997; 190(1):66–77.PubMedCrossRefGoogle Scholar
  70. 70.
    Kagitani F, Kuroiwa Y, Wakana S et al. Peg5/Neuronatin is an imprinted gene located on sub-distal chromosome 2 in the mouse. Nucleic Acids Res 1997; 25(17):3428–3432.PubMedCrossRefGoogle Scholar
  71. 71.
    Bastepe M, Frohlich 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(8):1255–1263.PubMedGoogle Scholar
  72. 72.
    Laspa E, Bastepe M, Jüppner H et al. Phenotypic and molecular genetic aspects of pseudohypoparathyroidism type ib in a Greek kindred: evidence for enhanced uric acid excretion due to parathyroid hormone resistance. J Clin Endocrinol Metab 2004;89(12):5942–5947.PubMedCrossRefGoogle Scholar
  73. 73.
    Mahmud FH, Linglart A, Bastepe M et al. Molecular diagnosis of pseudo hypoparathyroidism type Ib in a family with presumed paroxysmal dyskinesia. Pediatrics 2005; 115(2):e242–244.PubMedCrossRefGoogle Scholar
  74. 74.
    Liu J, Nealon JG, Weinstein LS. Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB. Hum Mol Genet 2005; 14(1):95–102.PubMedCrossRefGoogle Scholar
  75. 75.
    Simonsen A, Bremnes B, Ronning E et al. Syntaxin-16, a putative Golgi t-SNARE. Eur J Cell Biol 1998; 75(3):223–231.PubMedGoogle Scholar
  76. 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(3):673–679.PubMedCrossRefGoogle Scholar
  77. 77.
    Bastepe M, Frohlich 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(1):25–37.PubMedGoogle Scholar
  78. 78.
    Coombes C, Arnaud P, Gordon E et al. Epigenetic properties and identification of an imprint mark in the Nesp-Gnasxl domain of the mouse Gnas imprinted locus. Mol Cell Biol 2003; 23(16):5475–5488.PubMedCrossRefGoogle Scholar
  79. 79.
    Jan de Beur S, Ding C, Germain-Lee E et al. Discordance between genetic and epigenetic defects in pseudohypoparathyroidism type 1b revealed by inconsistent loss of maternal imprinting at GNAS1. Am J Hum Genet 2003; 73(2):314–322.PubMedCrossRefGoogle Scholar
  80. 80.
    Liu J, Chen M, Deng C et al. Identification of the control region for tissue-specific imprinting of the stimulatory G protein alpha-subunit. Proc Natl Acad Sci USA 2005; 102(15):5513–5518.PubMedCrossRefGoogle Scholar
  81. 81.
    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(8):894–899.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

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

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