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Horm Metab Res 2012; 44(10): 716-723
DOI: 10.1055/s-0032-1314842
Review
© Georg Thieme Verlag KG Stuttgart · New York

GNAS Epigenetic Defects and Pseudohypoparathyroidism: Time for a New Classification?

G. Mantovani
1   Department of Medical Sciences, Endocrinology and Diabetology Unit, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
,
F. M. Elli
1   Department of Medical Sciences, Endocrinology and Diabetology Unit, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
,
A. Spada
1   Department of Medical Sciences, Endocrinology and Diabetology Unit, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
› Author Affiliations
Further Information

Publication History

received 27 December 2011

accepted 07 May 2012

Publication Date:
06 June 2012 (online)

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Abstract

Pseudohypoparathyroidism-Ia and -Ib (PHP-Ia and -Ib) are caused by mutations in GNAS exons 1–13 and methylation defects in the imprinted GNAS cluster, respectively. PHP-Ia patients show Albright hereditary osteodystrophy (AHO), together with resistance to the action of different hormones that activate the Gs-coupled pathway. In PHP-Ib patients AHO is classically absent and hormone resistance is limited to PTH and TSH. This disorder is caused by GNAS methylation alterations with loss of imprinting at the exon A/B differentially methylated region (DMR) being the most consistent and recurrent defect. The familial form of the disease (AD-PHP-Ib) is typically associated with an isolated loss of imprinting at the exon A/B DMR due to microdeletions disrupting the upstream STX16 gene. In addition, deletions removing the entire NESP55 DMR, located within GNAS, associated with loss of all the maternal GNAS imprints have been identified in some AD-PHP-Ib kindreds. Conversely, most sporadic PHP-Ib cases have GNAS imprinting abnormalities that involve multiple DMRs, but the genetic lesion underlying these defects is unknown. Recently, methylation defects have been detected in a subset of patients with PHP-Ia and variable degrees of AHO, indicating a molecular overlap between the 2 forms. Imprinting defects do not seem to be associated with the severity of AHO neither with specific AHO signs. In conclusion, the latest findings on the molecular basis underlying these defects suggest the existence of a clinical and genetic/epigenetic overlap between PHP-Ia and PHP-Ib, and highlight the necessity of a new clinical classification of these disorders based on molecular findings.

Key words

pseudohypoparathyroidism - Albright hereditary osteodystrophy - GNAS - imprinting
 

  • References

  • 1 Albright F, Burnett CH, Smith CH, Parson W. Pseudohypoparathyroidism: an example of “Seabright-Bantam sindrome”. Endocrinol 1942; 30: 922-932
    Search in Google Scholar
  • 2 Mantovani G, Spada A. Mutations in the Gs alpha gene causing hormone resistance. Best Pract Res Clin Endocrinol Metab 2006; 20: 501-513
    CrossrefPubMedSearch in Google Scholar
  • 3 Mantovani G. Pseudohypoparathyroidism: Diagnosis and Treatment. J Clin Endocrinol Metab 2011; 96: 3020-3030
    Search in Google Scholar
  • 4 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 2001; 22: 675-705
    CrossrefPubMedSearch in Google Scholar
  • 5 Tashjian AH, Frantz AG, Lee JB. Pseudohypoparathyroidism: assays of parathyroid hormone and thyrocalcitonin. Proc Natl Acad Sci USA 1966; 56: 1138-1142
    CrossrefPubMedSearch in Google Scholar
  • 6 Mann JB, Alterman S, Hills AG. Albright’s hereditary osteodystrophy comprising pseudohypoparathyroidism and pseudopseudohypoparathyroidism with a report of two cases representing the complete syndrome occurring in successive generations. Ann Intern Med 1962; 56: 315-342
    CrossrefPubMedSearch in Google Scholar
  • 7 Drezner M, Neelon FA, Lebovitz HE. Pseudohypoparathyroidism type II: a possible defect in the reception of the cyclic AMP signal. New Eng J Med 1973; 289: 1056-1060
    CrossrefPubMedSearch in Google Scholar
  • 8 Stone MD, Hosking DJ, Garcia-Himmelstine C, White DA, Rosenblum D, Worth HG. The renal response to exogenous parathyroid hormone in treated pseudohypoparathyroidism. Bone 1993; 14: 727-735
    CrossrefPubMedSearch in Google Scholar
  • 9 Potts JT. Parathyroid hormone: past and present. J Endocrinol 2005; 18: 311-325
    PubMedSearch in Google Scholar
  • 10 Gensure RC, Gardella TJ, Jüppner H. Parathyroid hormone and parathyroid hormone-related peptide, and their receptors. Biochem Biophys Res Commun 2005; 328: 666-678
    CrossrefPubMedSearch in Google Scholar
  • 11 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
    Search in Google Scholar
  • 12 Moses AM, Weinstock RS, Levine MA, Breslau NA. Evidence for normal antidiuretic responses to endogenous and exogenous arginine vasopressein in patients with guanine nucleotide-binding stimulatory protein-deficient pseudohypoparathyroidism. J Clin Endocrinol Metab 1986; 62: 221-224
    CrossrefPubMedSearch in Google Scholar
  • 13 Faull CM, Welbury RR, Paul B, Kendall-Taylor P. Pseudohypoparathyroidism: its phenotypic variability and associated disorders in a large family. Q J Med 1991; 78: 251-264
    PubMedSearch in Google Scholar
  • 14 Kidd GS, Schaaf M, Adler RA, Lassman MN, Wray HL. Skeletal responsiveness in pseudohypoparathyroidism: a spectrum of clinical disease. Am J Med 1980; 68: 772-781
    CrossrefPubMedSearch in Google Scholar
  • 15 Murray TM, Rao LG, Wong MM, Waddell JP, McBroom R, Tam CS, Rosen F, Levine MA. 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
    PubMedSearch in Google Scholar
  • 16 Eubanks PJ, Stabile BE. Osteitis fibrosa cystica with renal parathyroid hormone resistance: a review of pseudohypoparathyroidism with insight into calcium homeostasis. Arch Surg 1998; 133: 673-676
    CrossrefPubMedSearch in Google Scholar
  • 17 Cohen RD, Vince FP. Pseudohypoparathyroidism with raised plasma alkaline phosphatase. Arch Dis Child 1969; 44: 96-101
    CrossrefPubMedSearch in Google Scholar
  • 18 Kolb FO, Steinbach HL. Pseudohypoparathyroidism with secondary hyperparathyroidism and osteitis fibrosa. J Clin Endocrinol Metab 1962; 22: 59-70
    CrossrefPubMedSearch in Google Scholar
  • 19 Tollin SR, Perlmutter S, Aloia JF. Serial changes in bone mineral density and bone turnover after correction of secondary hyperparathyroidism in a patient with pseudohypoparathyroidism type Ib. J Bone Miner Res 2000; 15: 1412-1416
    CrossrefPubMedSearch in Google Scholar
  • 20 Ish-Shalom S, Rao LG, Levine MA, Fraser D, Kooh SW, Josse RG, McBroom R Wong MM, Murray TM. Normal parathyroid hormone responsiveness of bone-derived cells from a patient with pseudohypoparathyroidism. J Bone Miner Res 1996; 11: 8-14
    Search in Google Scholar
  • 21 Burnstein MI, Kottamasu SR, Pettifor JM, Sochett E, Ellis BI, Frame B. Metabolic bone disease in pseudohypoparathyroidism: radiologic features. Radiology 1985; 155: 351-356
    PubMedSearch in Google Scholar
  • 22 Jacobson HG. Dense bone – too much bone: radiological considerations and differential diagnosis. Part I. Skeletal Radiol 1985; 13: 1-20
    CrossrefPubMedSearch in Google Scholar
  • 23 Balkissoon AR, Hayes CW. Case 14: intramedullary osteosclerosis. Radiology 1999; 212: 708-710
    PubMedSearch in Google Scholar
  • 24 Sbrocchi AM, Rauch F, Lawson ML, Hadjiyannakis S, Lawrence S, Bastepe M, Jüppner H, Ward LM. Osteosclerosis in two brothers with autosomal dominant pseudohypoparathyroidism type 1b: bone histomorphometric analysis. Eur J Endocrinol 2011; 164: 295-301
    CrossrefPubMedSearch in Google Scholar
  • 25 Long DN, Levine MA, Germain-Lee EL. Bone mineral density in pseudohypoparathyroidism type 1a. J Clin Endocrinol Metab 2010; 95: 4465-4475
    CrossrefPubMedSearch in Google Scholar
  • 26 Levine MA, Downs Jr RW, Singer M, Marx SJ, Aurbach GD, Spiegel AM. Deficient activity of guanine nucleotide regulatory protein in erythrocytes from patients with pseudohypoparathyroidism. Biochem Biophys Res Commun 1980; 94: 1319-1324
    CrossrefPubMedSearch in Google Scholar
  • 27 Farfel Z, Brickman AS, Kaslow HR, Brothers VM, Bourne HR. Defect of receptor-cyclase coupling protein in pseudohypoparathyroidism. New Eng J Med 1980; 303: 237-242
    CrossrefPubMedSearch in Google Scholar
  • 28 Levine MA, Downs Jr RW, Moses AM, Breslau NA, Marx SJ, Lasker RD, Rizzoli RE, Aurbach GD, Spiegel AM. Resistance to multiple hormones in patients with pseudohypoparathyroidism: association with deficient activity of guanine nucleotide regulatory protein. Am J Med 1983; 74: 545-556
    Search in Google Scholar
  • 29 Radeke HH, Auf’ mkolk B, Jüppner H, Krohn HP, Keck E, Hesch RD. Multiple pre- and postreceptor defects in pseudohypoparathyroidism (a multicenter study with 24 patients). J Clin Endocrinol Metab 1986; 62: 393-402
    CrossrefPubMedSearch in Google Scholar
  • 30 Barrett D, Breslau NA, Wax MB, Molinoff PB, Downs Jr RW. New form of pseudohypoparathyroidism with abnormal catalytic adenylate cyclase. Am J Physiol 1989; 257: E277-E283
    PubMedSearch in Google Scholar
  • 31 Silve C, Santora A, Breslau N, Moses A, Spiegel A. Selective resistance to parathyroid hormone in cultured skin fibroblasts from patients with pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab 1986; 62: 640-644
    CrossrefPubMedSearch in Google Scholar
  • 32 Eyre WG, Reed WB. Albright hereditary osteodystrophy with cutaneous bone formation. Arch Dermatol 1971; 104: 634-642
    CrossrefPubMedSearch in Google Scholar
  • 33 Farfel Z, Friedman E. Mental deficiency in pseudohypoparathyroidism type I is associated with Ns-protein deficiency. Ann Intern Med 1986; 105: 197-199
    CrossrefPubMedSearch in Google Scholar
  • 34 Long DN, McGuire S, Levine MA, Weinstein LS, Germain-Lee EL. 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: 1073-1079
    CrossrefPubMedSearch in Google Scholar
  • 35 Albright F, Forbes AP, Henneman PH. Pseudopseudohypoparathyroidism. Trans Assoc Am Physicians 1952; 65: 337-350
    PubMedSearch in Google Scholar
  • 36 Wemeau JL, Balavoine AS, Ladsous M, Velayoudom-Cephise FL, Vlaeminck-Guillem V. Multihormonal resistance to parathyroid hormone, thyroid stimulatin hormone, and other hormonal and neurosensory stimuli in patients with pseudohypoparathyroidism. J Pediatr Endocrinol Metab 2006; 19: 253-261
    CrossrefPubMedSearch in Google Scholar
  • 37 Germain-Lee EL. Short stature, obesity, and growth hormone deficiency in pseudohypoparathyroidism type Ia. Pediatr Endocrinol Rev 2006; 3: 318-326
    PubMedSearch in Google Scholar
  • 38 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 2001; 22: 675-705
    CrossrefPubMedSearch in Google Scholar
  • 39 Levine MA, Jap TS, Hung W. Infantile hypothyroidism in two sibs: an unusual presentation of pseudohypoparathyroidism type Ia. J Pediatr 1985; 107: 919-922
    CrossrefPubMedSearch in Google Scholar
  • 40 Pohlenz J, Ahrens W, Hiort O. A new heterozygous mutation (L338N) in the human Gsalpha (GNAS1) gene as a cause for congenital hypothyroidism in Albright’s hereditary osteodystrophy. Eur J Endocrinol 2003; 148: 463-468
    CrossrefPubMedSearch in Google Scholar
  • 41 Riepe FG, Ahrens W, Krone N, Fölster-Holst R, Brasch J, Sippell WG, Hiort O, Partsch CJ. Early manifestation of calcinosis cutis in pseudohypoparathyroidism type Ia associated with a novel mutation in the GNAS gene. Eur J Endocrinol 2005; 152: 515-519
    CrossrefPubMedSearch in Google Scholar
  • 42 Pinsker JE, Rogers W, McLean S, Schaefer FV, Fenton C. Pseudohypoparathyroidism type 1a with congenital hypothyroidism. J Pediatr Endocrinol Metab 2006; 19: 1049-1052
    CrossrefPubMedSearch in Google Scholar
  • 43 Mantovani G, Spada A. Resistance to growth hormone releasing hormone and gonadotropins in Albright’s hereditary osteodystrophy. J Pediatr Endocrinol Metab 2006; 19: 663-670
    Search in Google Scholar
  • 44 Mantovani G, Maghnie M, Weber G, De Menis E, Brunelli V, Cappa M, Loli P, Beck-Peccoz P, Spada A. Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type Ia: new evidence for imprinting of the Gs alpha gene. J Clin Endocrinol Metab 2003; 88: 4070-4074
    CrossrefPubMedSearch in Google Scholar
  • 45 Germain-Lee EL, Groman J, Crane JL, Jan de Beur SM, Levine MA. Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J Clin Endocrinol Metab 2003; 88: 4059-4069
    CrossrefPubMedSearch in Google Scholar
  • 46 de Sanctis L, Bellone J, Salerno M, Faleschini E, Caruso-Nicoletti M, Cicchetti M, Concolino D, Balsamo A, Buzi F, Ghizzoni L, de Sanctis C. GH secretion in a cohort of children with pseudohypoparathyroidism type Ia. J Endocrinol Invest 2007; 30: 97-103
    PubMedSearch in Google Scholar
  • 47 Tsai KS, Chang CC, Wu DJ, Huang TS, Tsai IH, Chen FW. 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: 450-455
    PubMedSearch in Google Scholar
  • 48 Vlaeminck-Guillem V, D’herbomez M, Pigny P, Fayard A, Bauters C, Decoulx M, Wémeau JL. Pseudohypoparathyroidism Ia and hypercalcitoninemia. J Clin Endocrinol Metab 2001; 86: 3091-3096
    CrossrefPubMedSearch in Google Scholar
  • 49 Carel JC, Le Stunff C, Condamine L, Mallet E, Chaussain JL, Adnot P, Garabedian M, Bougnères P. Resistance to the lipolytic action of epinephrine: a new feature of protein Gs deficiency. J Clin Endocrinol Metab 1999; 84: 4127-4131
    CrossrefPubMedSearch in Google Scholar
  • 50 Farfel Z, Brothers VM, Brickman AS, Conte F, Neer R, Bourne HR. Pseudohypoparathyroidism: inheritance of deficient receptor-cyclase coupling activity. Proceedings of National Academy of Sciences USA 1981; 78: 3098-3102
    CrossrefPubMedSearch in Google Scholar
  • 51 Fitch N. Albright’s hereditary osteodistrophy: a Review. Am J Med Gen 1982; 11: 11-29
    CrossrefPubMedSearch in Google Scholar
  • 52 Weinberg AG, Stone RT. Autosomal dominant inheritance in Albright’s hereditary osteodystrophy. J Ped 1971; 79: 996-999
    CrossrefPubMedSearch in Google Scholar
  • 53 Hayward BE, Barlier A, Korbonits M, Grossman AB, Jacquet P, Enjalbert A, Bonthron DT. Imprinting of the Gαs gene GNAS in the pathogenesis of acromegaly. J Clin Invest 2001; 107: R31-R36
    Search in Google Scholar
  • 54 Mantovani G, Ballare E, Giammona E, Beck-Peccoz P, Spada A. The Gs alpha gene: predominant maternal origin of transcription in human thyroid gland and gonads. J Clin Endocrinol Metab 2002; 87: 4736-4740
    Search in Google Scholar
  • 55 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 2002; 296: 67-72
    Search in Google Scholar
  • 56 Liu J, Erlichman B, Weinstein LS. The stimulatory G protein α-subunit Gsα is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1 A and 1B. J Clin Endocrinol Metab 2003; 88: 4336-4341
    CrossrefPubMedSearch in Google Scholar
  • 57 Mann JB, Alterman S, Hills AG. Albright’s hereditary osteodystrophy comprising pseudohypoparathyroidism and pseudopseudohypoparathyroidism with a report of two cases representing the complete syndrome occurring in successive generations. Ann Intern Med 1962; 56: 315-342
    CrossrefPubMedSearch in Google Scholar
  • 58 Levine MA, Jap TS, Mauseth RS, Downs RV, Spiegel AM. Activity of the stimulatory guanine nucleotide-binding protein is reduced in erythrocytes from patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism: biochemical, endocrine, and genetic analysis of Albright’s hereditary osteodystrophy in six kindreds. J Clin Endocrinol Metab 1986; 62: 497-502
    CrossrefPubMedSearch in Google Scholar
  • 59 Al-Salameh A, Despert F, Kottler ML, Linglart A, Carel JC, Lecomte P. Resistance to epinephrine and hypersensitivity (hyperresponsiveness) to CB1 antagonists in a patient with pseudohypoparathyroidism type Ic. Eur J Endocrinol 2010; 162: 819-824
    CrossrefPubMedSearch in Google Scholar
  • 60 Fischer JA, Bourne HR, Dambacher MA, Tschopp F, De Meyer R, Devogelaer JP, Werder EA, Nagant De Deuxchaisnes C. Pseudohypoparathyroidism: inheritance and expression of deficient receptor-cyclase coupling protein activity. Clin Endocrinol 1983; 19: 747-754
    CrossrefPubMedSearch in Google Scholar
  • 61 Wilson LC, Leverton K, Oude Luttikhuis ME, Oley CA, Flint J, Wolstenholme J, Duckett DP, Barrow MA, Leonard JV, Read AP, Trembath RC. Brachydactyly and mental retardation: an Albright’s hereditary osteodystrophy-like syndrome localized to 2q37. Am J Hum Genet 1995; 56: 400-407
    Search in Google Scholar
  • 62 Phelan MC, Rogers RC, Clarkson KB, Bowyer FP, Levine MA, Estabrooks LL, Severson MC, Dobyns WB. Albright’s hereditary osteodystrophy and del(2)(q37.3) in four unrelated individuals. Am J Hum Genet 1995; 58: 1-7
    PubMedSearch in Google Scholar
  • 63 Weinstein LS. Albright hereditary osteodystrophy, pseudohypoparathyroidism, and Gs deficiency. In: Spiegel AM. (ed.). G proteins, receptors, and disease. Totowa, New Jersey: Humana Press; 1998: 23-56
    CrossrefSearch in Google Scholar
  • 64 Winter JS, Hughes IA. Familial pseudohypoparathyroidism without somatic anomalies. Canad Med Ass J 1986; 123: 26-31
    PubMedSearch in Google Scholar
  • 65 Nusynowitz ML, Frame B, Kolb FO. The spectrum of the hypoparathyroid states: a classification based on physiologic principles. Medicine 1976; 55: 105-119
    CrossrefPubMedSearch in Google Scholar
  • 66 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 2007; 67: 822-831
    CrossrefPubMedSearch in Google Scholar
  • 67 Schipani E, Weinstein LS, Bergwitz C, Iida-Klein A, Kong XF, Stuhrmann M, Kruse K, Whyte MP, Murray T, Schmidtke J. 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
    CrossrefPubMedSearch in Google Scholar
  • 68 Bettoun JD, Minagawa M, Kwan MY, Lee HS, Yasuda T, Hendy GN, Goltzman D, White JH. 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. J Clin Endocrinol Metab 1997; 82: 1031-1040
    CrossrefPubMedSearch in Google Scholar
  • 69 Fukumoto S, Suzawa M, Takeuchi Y, Kodama Y, Nakayama K, Ogata E, Matsumoto T, Fujita T. 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
    CrossrefPubMedSearch in Google Scholar
  • 70 Lanske B, Karaplis AC, Lee K, Luz A, Vortkamp A, Pirro A, Karperien M, Defize LH, Ho C, Mulligan RC, Abou-Samra AB, Jüppner H, Segre GV, Kronenberg HM. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 1996; 273: 663-666
    CrossrefPubMedSearch in Google Scholar
  • 71 Jobert AS, Zhang P, Couvineau A, Bonaventure J, Roume J, Le Merrer M, Silve C. Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodisplasia. J Clin Invest 1998; 102: 34-40
    CrossrefPubMedSearch in Google Scholar
  • 72 Mantovani G, Bondioni S, Linglart A, Maghnie M, Cisternino M, Corbetta S, Lania AG, Beck-Peccoz P, Spada A. Genetic analysis and evaluation of resistance to thyrotropin and growth hormone-releasing hormone in pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab 2007; 92: 3738-3742
    Search in Google Scholar
  • 73 Bastepe M, Weinstein LS, Ogata N, Kawaguchi H, Juppner H, Kronenberg HM, Chung UI. Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Proc Natl Acad Sci USA 2004; 101: 14794-14799
    CrossrefPubMedSearch in Google Scholar
  • 74 Kelsey G. Imprinting on chromosome 20: tissue-specific imprinting and imprinting mutations in the GNAS locus. Am J Med Genet Part C 2010; 154C: 377-386
    CrossrefPubMedSearch in Google Scholar
  • 75 Mantovani G, Bondioni S, Locatelli M, Pedroni C, Lania AG, Ferrante E, Filopanti M, Beck-Peccoz P, Spada A. Biallelic expression of the Gs alpha gene in human bone and adipose tissue. J Clin Endocrinol Metab 2004; 89: 6316-6319
    CrossrefPubMedSearch in Google Scholar
  • 76 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 2001; 86: 4627-4629
    CrossrefPubMedSearch in Google Scholar
  • 77 Gejman PV, Weinstein LS, Martinez M, Spiegel AM, Cao Q, Hsieh WT, Hoehe MR, Gershon ES. Genetic mapping of the Gs α-subunit gene (GNAS) to the distal long arm of chromosome 20 using a polymorphism detected by denaturating gradient gel electrophoresis. Genomics 1991; 9: 782-783
    CrossrefPubMedSearch in Google Scholar
  • 78 Weinstein LS, Gejman PV, de Mazancourt P, American N, Spiegel AM. A heterozygous 4-bp deletion mutation in the Gs alpha gene (GNAS) in a patient with Albright’s hereditary osteodystrophy. Genomics 1992; 13: 1319-1321
    CrossrefPubMedSearch in Google Scholar
  • 79 Ahmed SF, Dixon PH, Bonthron DT, Stirling HF, Barr DG, Kelnar CJ, Thakker RV. GNAS mutational analysis in pseudohypoparathyroidism. Clin Endocrinol 1998; 49: 525-531
    CrossrefPubMedSearch in Google Scholar
  • 80 Mantovani G, Romoli R, Weber G, Brunelli V, De Menis E, Beccio S, Beck-Peccoz P, Spada A. Mutational analysis of GNAS1 in patients with pseudohypoparathyroidism: identification of two novel mutations. J Clin Endocrinol Metab 2000; 85: 4243-4248
    CrossrefPubMedSearch in Google Scholar
  • 81 Aldred MA, Trembath RC. Activating and inactivating mutations in the human GNAS gene. Hum Mut 2000; 16: 183-189
    CrossrefPubMedSearch in Google Scholar
  • 82 Yokoyama M, Takeda K, Iyota K, Okabayashi T, Hashimoto K. A 4-bp deletion mutation of Gs alpha gene in a Japanese patient with pseudoparathyroidism. J Endocrinol Invest 1996; 19: 236-241
    PubMedSearch in Google Scholar
  • 83 Yu S, Yu D, Hainline BE, Brener JL, Wilson KA, Wilson LC, Oude-Luttikhuis ME, Trembath RC, Weinstein LS. A deletion hot-spot in exon 7 of the Gsα gene (GNAS ) in patients with Albright hereditary osteodystrophy. Hum Mol Genet 1995; 4: 2001-2002
    CrossrefPubMedSearch in Google Scholar
  • 84 Juppner H, Schipani E, Bastepe M, Cole DE, Lawson ML, Mannstadt M, Hendy GN, Plotkin H, Koshiyama H, Koh T, Crawford JD, Olsen BR, Vikkula M. The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3. Proc Nat Acad Sci USA 1998; 95: 11798-11803
    CrossrefPubMedSearch in Google Scholar
  • 85 Wu WI, Schwindinger WF, Aparicio LF, Levine MA. Selective resistance to parathyroid hormone caused by a novel uncoupling mutation in the carboxyl terminus of Gsα: a cause of pseudohypoparathyroidism type Ib. J Biol Chem 2001; 276: 165-171
    PubMedSearch in Google Scholar
  • 86 Maupetit-Méhouas S, Mariot V, Reynès C, Bertrand G, Feillet F, Carel JC, Simon D, Bihan H, Gajdos V, Devouge E, Shenoy S, Agbo-Kpati P, Ronan A, Naud-Saudreau C, Lienhardt A, Silve C, Linglart A. Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib. J Med Genet 2011; 48: 55-63
    CrossrefPubMedSearch in Google Scholar
  • 87 Liu J, Litman D, Rosenberg MJ, Yu S, Biesecker LG, Weinstein LS. A GNAS imprinting defect in pseudohypoparathyroidism type Ib. J Clin Invest 2000; 106: 1167-1174
    Search in Google Scholar
  • 88 Bastepe M, Pincus JE, Sugimoto T, Tojo K, Kanatani M, Azuma Y, Kruse K, Rosenbloom AL, Koshiyama H, Jüppner H. 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 GNAS locus. Hum Mol Genet 2001; 10: 1231-1241
    CrossrefPubMedSearch in Google Scholar
  • 89 Bastepe M, Fröhlich LF, Hendy GN, Indridason OS, Josse RG, Koshiyama H, Körkkö J, Nakamoto JM, Rosenbloom AL, Slyper AH, Sugimoto T, Tsatsoulis A, Crawford JD, Jüppner H. 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: 1255-1263
    CrossrefPubMedSearch in Google Scholar
  • 90 Linglart A, Gensure RC, Olney RC, Jüppner H, Bastepe M. 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: 804-814
    CrossrefPubMedSearch in Google Scholar
  • 91 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 2005; 37: 25-27
    CrossrefPubMedSearch in Google Scholar
  • 92 Chillambhi S, Turan S, Hwang DY, Chen HC, Juppner H, Bastepe M. Deletion of the noncoding GMAS antisense transcript causes pseudohypoparathyroidism type I band biparental defects of GNAS methylation in cis. J Clin Endocrinol Metab 2010; 95: 3993-4002
    CrossrefPubMedSearch in Google Scholar
  • 93 Fröhlich LF, Mrakovcic M, Steinborn R, Chung UI, Bastepe M, Jüppner H. 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 USA 2010; 107: 9275-9280
    CrossrefPubMedSearch in Google Scholar
  • 94 Williamson CM, Turner MD, Ball ST, Nottingham WT, Glenister P, Fray M, Tymowska-Lalanne Z, Plagge A, Powles-Glover N, Kelsey G, Maconochie M, Peters J. Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster. Nat Genet 2006; 38: 350-355
    CrossrefPubMedSearch in Google Scholar
  • 95 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
    CrossrefPubMedSearch in Google Scholar
  • 96 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
    CrossrefPubMedSearch in Google Scholar
  • 97 Lecumberri B, Fernández-Rebollo E, Sentchordi L, Saavedra P, Bernal-Chico A, Pallardo LF, Bustos JM, Castaño L, de Santiago M, Hiort O, Pérez de Nanclares G, Bastepe M. 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: 276-280
    CrossrefPubMedSearch in Google Scholar
  • 98 Fernández-Rebollo E, Lecumberri B, Garin I, Arroyo J, Bernal-Chico A, Goñi F, Orduña R, Spanish PHP Group. Castaño L, de Nanclares GP. New mechanisms involved in paternal 20q disomy associated with pseudohypoparathyroidism. Eur J Endocrinol 2010; 163: 953-962
    CrossrefPubMedSearch in Google Scholar
  • 99 Bastepe M, Altug-Teber O, Agarwal C, Oberfield SE, Bonin M, Jüppner H. Paternal uniparental isodisomy of the entire chromosome 20 as a molecular cause of pseudohypoparathyroidism type Ib (PHP-Ib). Bone 2011; 48: 659-662
    CrossrefPubMedSearch in Google Scholar
  • 100 de Nanclares GP, Fernández-Rebollo E, Santin I, García-Cuartero B, Gaztambide S, Menéndez E, Morales MJ, Pombo M, Bilbao JR, Barros F, Zazo N, Ahrens W, Jüppner H, Hiort O, Castaño L, Bastepe M. Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright hereditary osteodystrophy. J Clin Endocrinol Metab 2007; 92: 2370-2373
    Search in Google Scholar
  • 101 Mariot V, Maupetit-Méhouas S, Sinding C, Kottler ML, Linglart A. A maternal epimutation of GNAS leads to Albright osteodystrophy and parathyroid hormone resistance. J Clin Endocrinol Metab 2008; 93: 661-665
    Search in Google Scholar
  • 102 Unluturk U, Harmanci A, Babaoglu M, Yasar U, Varli K, Bastepe M, Bayraktar M. Molecular diagnosis and clinical characterization of pseudohypoparathyroidism type-Ib in a patient with mild Albright hereditary osteodystrophy-like features, epileptic seizures, and defective renal handling of uric acid. Am J Med Sci 2008; 336: 84-90
    CrossrefPubMedSearch in Google Scholar
  • 103 Mantovani G, de Sanctis L, Barbieri AM, Elli FM, Bollati V, Vaira V, Labarile P, Bondioni S, Peverelli E, Lania AG, Beck-Peccoz P, Spada A. Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of Albright hereditary osteodystrophy and molecular analysis in 40 patients. J Clin Endocrinol Metab 2010; 95: 651-658
    Search in Google Scholar
  • 104 Zazo C, Thiele S, Martín C, Fernandez-Rebollo E, Martinez-Indart L, Werner R, Garin I, Spanish PHP Group. Hiort O, Perez de Nanclares G. Gsα activity is reduced in erythrocyte membranes of patients with pseudohypoparathyrodism due to epigenetic alterations at the GNAS locus. J Bone Miner Res 2011; 26: 1864-1870
    CrossrefPubMedSearch in Google Scholar
  • 105 Thiele S, de Sanctis L, Werner R, Grötzinger J, Aydin C, Jüppner H, Bastepe M, Hiort O. 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: 653-660
    CrossrefPubMedSearch in Google Scholar
  • 106 Linglart A, Carel JC, Garabédian M, Lé T, Mallet E, Kottler ML. 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: 189-197
    CrossrefPubMedSearch in Google Scholar
  • 107 Shore EM, Ahn J, 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. New Engl J Med 2002; 346: 99-106
    CrossrefPubMedSearch in Google Scholar
  • 108 Adegbite NS, Xu M, Kaplan FS, Shore EM, Pignolo RJ. Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am J Med Genet A 2008; 146A: 1788-1796
    CrossrefPubMedSearch in Google Scholar