Skip to main content
SpringerLink
Log in

Pseudohypoparathyroidism: one gene, several syndromes

  • Review
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome 20q13.3 that undergoes parent-specific methylation changes at several sites. GNAS encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. Heterozygous inactivating mutations involving the maternal GNAS exons 1–13 cause PHP type Ia (PHP1A). Because of much reduced paternal Gsα expression in certain tissues, such as the proximal renal tubules, thyroid, and pituitary, there is little or no Gsα protein in the presence of maternal GNAS mutations, thus leading to PTH-resistant hypocalcemia and hyperphosphatemia. When located on the paternal allele, the same or similar GNAS mutations are the cause of PPHP. Besides biochemical abnormalities, patients affected by PHP1A show developmental abnormalities, referred to as Albrights hereditary osteodystrophy (AHO). Some, but not all of these AHO features are encountered also in patients affected by PPHP, who typically show no laboratory abnormalities. Autosomal dominant PHP type Ib (AD-PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16, which are associated with loss-of-methylation (LOM) at exon A/B alone or at all maternally methylated GNAS exons. LOM at exon A/B and the resulting biallelic expression of A/B transcripts reduces Gsα expression, thus leading to hormonal resistance. Epigenetic changes at all differentially methylated GNAS regions are also observed in sporadic PHP1B, the most frequent disease variant, which remains unresolved at the molecular level, except for rare cases with paternal uniparental isodisomy or heterodisomy of chromosome 20q (patUPD20q).

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

Similar content being viewed by others

References

  1. Albright F et al (1942) Pseudohypoparathyroidism—an example of “Seabright-Bantam syndrome”. Endocrinology 30:922–932

    CAS  Google Scholar 

  2. Tashjian AH Jr, Frantz AG, Lee JB (1966) Pseudohypoparathyroidism: assays of parathyroid hormone and thyrocalcitonin. Proc Natl Acad Sci USA 56:1138–1142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Albright F, Forbes AP, Henneman PH (1952) Pseudo-pseudohypoparathyroidism. Trans Assoc Am Physicians 65:337–350

    CAS  PubMed  Google Scholar 

  4. Chase LR, Melson GL, Aurbach GD (1969) Pseudohypoparathyroidism: defective excretion of 3′,5′-AMP in response to parathyroid hormone. J Clin Invest 48(10):1832–1844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Levine MA et al (1980) Deficient activity of guanine nucleotide regulatory protein in erythrocytes from patients with pseudohypoparathyroidism. Biochem Biophys Res Commun 94:1319–1324

    Article  CAS  PubMed  Google Scholar 

  6. Farfel Z et al (1980) Defect of receptor-cyclase coupling protein in pseudohypoparathyroidism. N Engl J Med 303:237–242

    Article  CAS  PubMed  Google Scholar 

  7. Levine MA et al (1986) 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 62:497–502

    Article  CAS  PubMed  Google Scholar 

  8. Levine MA et al (1983) Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein. Am J Med 74:545–556

    Article  CAS  PubMed  Google Scholar 

  9. Blatt C et al (1988) Chromosomal localization of genes encoding guanine nucleotide-binding protein subunits in mouse and human. Proc Natl Acad Sci USA 85(20):7642–7646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kozasa T et al (1988) Isolation and characterization of the human Gsα gene. Proc Natl Acad Sci USA 85:2081–2085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Weinstein LS et al (1990) Mutations of the Gs α-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc Natl Acad Sci USA 87:8287–8290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Patten JL et al (1990) Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright’s hereditary osteodystrophy. N Engl J Med 322:1412–1419

    Article  CAS  PubMed  Google Scholar 

  13. Turan S et al (2015) Evidence of hormone resistance in a pseudo-pseudohypoparathyroidism patient with a novel paternal mutation in GNAS. Bone 71:53–57

    Article  CAS  PubMed  Google Scholar 

  14. Davies AJ, Hughes HE (1993) Imprinting in Albright’s hereditary osteodystrophy. J Med Genet 30:101–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wilson LC et al (1994) Parental origin of Gsα gene mutations in Albright’s hereditary osteodystrophy. J Med Genet 31:835–839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Levine MA (2002) Pseudohypoparathyroidism. In: Raisz LG, Bilezikian JP, Rodan GA (eds) Principles of bone biology. Academic Press, New York, pp 1137–1159

    Chapter  Google Scholar 

  17. Thiele S et al (2011) Functional characterization of GNAS mutations found in patients with pseudohypoparathyroidism type Ic defines a new subgroup of pseudohypoparathyroidism affecting selectively Gsalpha-receptor interaction. Hum Mutat 32(6):653–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Linglart A et al (2002) GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance. J Clin Endocrinol Metab 87(1):189–197

    Article  CAS  PubMed  Google Scholar 

  19. Kaplan FS, Shore EM (2000) Progressive osseous heteroplasia. J Bone Miner Res 15(11):2084–2094

    Article  CAS  PubMed  Google Scholar 

  20. Winter JSD, Hughes IA (1980) Familial pseudohypoparathyroidism without somatic anomalities. Can Med Assoc J 123:26–31

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Weinstein L et al (2001) Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr Rev 22:675–705

    CAS  PubMed  Google Scholar 

  22. Schipani E, Kruse K, Jüppner H (1995) A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 268(5207):98–100

    Article  CAS  PubMed  Google Scholar 

  23. Bettoun JD et al (1997) 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 82:1031–1040

    CAS  PubMed  Google Scholar 

  24. Suarez F et al (1995) Expression and modulation of the parathyroid hormone (PTH)/PTH-related peptide receptor messenger ribonucleic acid in skin fibroblasts from patients with type Ib pseudohypoparathyroidism. J Clin Endocrinol Metab 80:965–970

    CAS  PubMed  Google Scholar 

  25. Fukumoto S et al (1996) Absence of mutations in parathyroid hormone (PTH)/PTH-related protein receptor complementary deoxyribonucleic acid in patients with pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab 81:2554–2558

    CAS  PubMed  Google Scholar 

  26. Jüppner H et al (1998) The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3. Proc Natl Acad Sci USA 95(20):11798–11803

    Article  PubMed  PubMed Central  Google Scholar 

  27. Liu J et al (2000) A GNAS1 imprinting defect in pseudohypoparathyroidism type IB. J Clin Invest 106:1167–1174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bastepe M et al (2001) Positional dissociation between the genetic mutation responsible for pseudohypoparathyroidism type Ib and the associated methylation defect at exon A/B: evidence for a long-range regulatory element within the imprinted GNAS1 locus. Hum Mol Genet 10(12):1231–1241

    Article  CAS  PubMed  Google Scholar 

  29. Ablow RC, Hsia YE, Brandt IK (1977) Acrodysostosis coinciding with pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism. Am J Roentgenol 128(1):95–99

    Article  CAS  Google Scholar 

  30. Graham JM Jr et al (2001) Radiographic findings and Gs-alpha bioactivity studies and mutation screening in acrodysostosis indicate a different etiology from pseudohypoparathyroidism. Pediatr Radiol 31(1):2–9

    Article  PubMed  Google Scholar 

  31. Wilson LC et al (1997) Normal erythrocyte membrane Gs alpha bioactivity in two unrelated patients with acrodysostosis. J Med Genet 34(2):133–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Linglart A et al (2011) Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. N Engl J Med 364(23):2218–2226

    Article  CAS  PubMed  Google Scholar 

  33. Michot C et al (2012) Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. Am J Hum Genet 90(4):740–745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Elli FM et al (2016) The prevalence of GNAS deficiency-related diseases in a large cohort of patients characterized by the EuroPHP network. J Clin Endocrinol Metab 101:3657–3668

    Article  PubMed  Google Scholar 

  35. Blomstrand S, Claësson I, Säve-Söderbergh J (1985) A case of lethal congenital dwarfism with accelerated skeletal maturation. Pediatr Radiol 15:141–143

    Article  CAS  PubMed  Google Scholar 

  36. Jobert AS et al (1998) Absence of functional receptors parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia. J Clin Invest 102:34–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Klopocki E et al (2010) Deletion and point mutations of PTHLH cause brachydactyly type E. Am J Hum Genet 86(3):434–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Thomas-Teinturier C et al (2016) Report of two novel mutations in PTHLH associated with brachydactyly type E and literature review. Am J Med Genet A 170(3):734–742

    Article  CAS  PubMed  Google Scholar 

  39. Thiele S et al (2016) From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the European EuroPHP network. Eur J Endocrinol 175:1–17

    Article  CAS  Google Scholar 

  40. Peters J et al (1994) Mapping studies of the distal imprinting region of mouse chromosome 2. Genet Res 63(3):169–174

    Article  CAS  PubMed  Google Scholar 

  41. Gejman PV et al (1991) Genetic mapping of the Gs-α subunit gene (GNAS1) to the distal long arm of chromosome 20 using a polymorphism detected by denaturing gradient gel electrophoresis. Genomics 9:782–783

    Article  CAS  PubMed  Google Scholar 

  42. Rao VV, Schnittger S, Hansmann I (1991) G protein Gs alpha (GNAS 1), the probable candidate gene for Albright hereditary osteodystrophy, is assigned to human chromosome 20q12-q13.2. Genomics 10(1):257–261

    Article  CAS  PubMed  Google Scholar 

  43. Levine MA, Modi WS, O’Brien SJ (1991) Mapping of the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase (GNAS1) to 20q13.2 → q13.3 in human by in situ hybridization. Genomics 11(2):478–479

    Article  CAS  PubMed  Google Scholar 

  44. Liu J et al (2000) Identification of a methylation imprint mark within the mouse Gnas locus. Mol Cell Biol 20(16):5808–5817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  46. Hayward B et al (2001) Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly. J Clin Invest 107:R31–R36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mantovani G et al (2002) The gsalpha gene: predominant maternal origin of transcription in human thyroid gland and gonads. J Clin Endocrinol Metab 87(10):4736–4740

    Article  CAS  PubMed  Google Scholar 

  48. Ischia R et al (1997) Molecular cloning and characterization of NESP55, a novel chromogranin-like precursor of a peptide with 5-HT1B receptor antagonist activity. J Biol Chem 272:11657–11662

    Article  CAS  PubMed  Google Scholar 

  49. Hayward B et al (1998) The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc Natl Acad Sci USA 95:10038–10043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Peters J et al (1999) A cluster of oppositely imprinted transcripts at the Gnas locus in the distal imprinting region of mouse chromosome 2. Proc Natl Acad Sci USA 96:3830–3835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Klemke M et al (2000) Characterization of the extra-large G protein alpha-subunit XLalphas. II. Signal transduction properties. J Biol Chem 275:33633–33640

    Article  CAS  PubMed  Google Scholar 

  52. Bastepe M et al (2002) Receptor-mediated adenylyl cyclase activation through XLalpha(s), the extra-large variant of the stimulatory G protein alpha-subunit. Mol Endocrinol 16(8):1912–1919

    Article  CAS  PubMed  Google Scholar 

  53. Lovisetti-Scamihorn P et al (1999) Relative amounts and molecular forms of NESP55 in various bovine tissues. Brain Res 829(1–2):99–106

    Article  CAS  PubMed  Google Scholar 

  54. Li T et al (2000) Tissue-specific expression of antisense and sense transcripts at the imprinted Gnas locus. Genomics 69(3):295–304

    Article  CAS  PubMed  Google Scholar 

  55. Ishikawa Y et al (1990) Alternative promoter and 5′ exon generate a novel Gsα mRNA. J Biol Chem 265:8458–8462

    CAS  PubMed  Google Scholar 

  56. Swaroop A et al (1991) Differential expression of novel Gs alpha signal transduction protein cDNA species. Nucleic Acids Res 19(17):4725–4729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Liu J et al (2000) Identification of a methylation imprint mark within the mouse Gnas locus. Mol Cell Biol 20:5808–5817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Puzhko S et al (2011) Parathyroid hormone signaling via Galphas is selectively inhibited by an NH(2)-terminally truncated Galphas: implications for pseudohypoparathyroidism. J Bone Miner Res 26(10):2473–2485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hayward B, Bonthron D (2000) An imprinted antisense transcript at the human GNAS1 locus. Hum Mol Genet 9:835–841

    Article  CAS  PubMed  Google Scholar 

  60. Wroe SF et al (2000) An imprinted transcript, antisense to Nesp, adds complexity to the cluster of imprinted genes at the mouse Gnas locus. Proc Natl Acad Sci USA 97(7):3342–3346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Coombes C et al (2003) Epigenetic properties and identification of an imprint mark in the Nesp-Gnasxl domain of the mouse Gnas imprinted locus. Mol Cell Biol 23(16):5475–5488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Long DN et al (2007) 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 92(3):1073–1079

    Article  CAS  PubMed  Google Scholar 

  63. Mouallem M et al (2008) Cognitive impairment is prevalent in pseudohypoparathyroidism type Ia, but not in pseudopseudohypoparathyroidism: possible cerebral imprinting of Gsalpha. Clin Endocrinol (Oxf) 68(2):233–239

    CAS  Google Scholar 

  64. Turan S et al (2014) Postnatal establishment of allelic Galphas silencing as a plausible explanation for delayed onset of parathyroid hormone resistance owing to heterozygous Galphas disruption. J Bone Miner Res 29(3):749–760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Marx SJ, Hershman JM, Aurbach GD (1971) Thyroid dysfunction in pseudohypoparathyroidism. J Clin Endocrinol Metab 33(5):822–828

    Article  CAS  PubMed  Google Scholar 

  66. Mantovani G et al (2003) Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type ia: new evidence for imprinting of the Gs alpha gene. J Clin Endocrinol Metab 88(9):4070–4074

    Article  CAS  PubMed  Google Scholar 

  67. Vigone MC, Di Frenna M, Weber G (2015) Heterogeneous phenotype in children affected by non-autoimmune hypothyroidism: an update. J Endocrinol Invest 38(8):835–840

    Article  CAS  PubMed  Google Scholar 

  68. Levine MA, Jap TS, Hung W (1985) Infantile hypothyroidism in two sibs: an unusual presentation of pseudohypoparathyroidism type Ia. J Pediatr 107(6):919–922

    Article  CAS  PubMed  Google Scholar 

  69. Faull CM et al (1991) Pseudohypoparathyroidism: its phenotypic variability and associated disorders in a large family. Q J Med 78(287):251–264

    CAS  PubMed  Google Scholar 

  70. Moses AM et al (1986) 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 62(1):221–224

    Article  CAS  PubMed  Google Scholar 

  71. Kaplan FS, Hahn GV, Zasloff MA (1994) Heterotopic ossification: two rare forms and what they can teach us. J Am Acad Orthop Surg 2(5):288–296

    Article  CAS  PubMed  Google Scholar 

  72. Shore E et al (2002) Paternally-inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med 346:99–106

    Article  CAS  PubMed  Google Scholar 

  73. Ahmed SF, Barr DG, Bonthron DT (2002) GNAS1 mutations and progressive osseous heteroplasia. N Engl J Med 346(21):1669–1671

    Article  PubMed  Google Scholar 

  74. Eddy MC et al (2000) Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification. J Bone Miner Res 15(11):2074–2083

    Article  CAS  PubMed  Google Scholar 

  75. Adegbite NS et al (2008) Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am J Med Genet A 146A(14):1788–1796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yu S et al (1995) A deletion hot-spot in exon 7 of the Gs alpha gene (GNAS1) in patients with Albright hereditary osteodystrophy. Hum Mol Genet 4(10):2001–2002

    Article  CAS  PubMed  Google Scholar 

  77. Lemos MC, Thakker RV (2015) GNAS mutations in Pseudohypoparathyroidism type 1a and related disorders. Hum Mutat 36(1):11–19

    Article  CAS  PubMed  Google Scholar 

  78. Elli FM et al (2013) Pseudohypoparathyroidism type Ia and pseudo-pseudohypoparathyroidism: the growing spectrum of GNAS inactivating mutations. Hum Mutat 34(3):411–416

    Article  CAS  PubMed  Google Scholar 

  79. Richard N et al (2013) Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLalphas in fetal development. J Clin Endocrinol Metab 98(9):E1549–E1556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Liu J, Erlichman B, Weinstein L (2003) 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 Metab 88:4336–4341

    Article  CAS  PubMed  Google Scholar 

  81. de Nanclares GP et al (2007) Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright’s hereditary osteodystrophy. J Clin Endocrinol Metab 92(6):2370–2373

    Article  PubMed  CAS  Google Scholar 

  82. Mariot V et al (2008) A maternal epimutation of GNAS leads to Albright osteodystrophy and parathyroid hormone resistance. J Clin Endocrinol Metab 93(3):661–665

    Article  CAS  PubMed  Google Scholar 

  83. Unluturk U et al (2008) 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 336(1):84–90

    Article  PubMed  Google Scholar 

  84. Mantovani G et al (2010) Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of Albright hereditary osteodystrophy and molecular analysis in 40 patients. J Clin Endocrinol Metab 95(2):651–658

    Article  CAS  PubMed  Google Scholar 

  85. Takatani R et al (2016) Analysis of multiple families with single individuals affected by pseudohypoparathyroidism type Ib (PHP1B) reveals only one novel maternally inherited GNAS deletion. J Bone Miner Res 31:796–805

    Article  CAS  PubMed  Google Scholar 

  86. Sharma A, Phillips AJ, Jüppner H (2015) Hypoplastic metatarsals—beyond cosmesis. N Engl J Med 373(22):2189–2190

    Article  PubMed  PubMed Central  Google Scholar 

  87. Zazo C et al (2011) Gsα activity is reduced in erythrocyte membranes of patients with pseudohypoparathyroidism due to epigenetic alterations at the GNAS locus. J Bone Miner Res 26:1864–1870

    Article  CAS  PubMed  Google Scholar 

  88. Turan S, Bastepe M (2013) The GNAS complex locus and human diseases associated with loss-of-function mutations or epimutations within this imprinted gene. Horm Res Paediatr 80(4):229–241

    Article  CAS  PubMed  Google Scholar 

  89. de Jan de Beur S et al (2003) Discordance between genetic and epigenetic defects in pseudohypoparathyroidism type 1b revealed by inconsistent loss of maternal imprinting at GNAS1. Am J Hum Genet 73:314–322

    Article  PubMed  PubMed Central  Google Scholar 

  90. Maupetit-Mehouas S et al (2011) Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib. J Med Genet 48(1):55–63

    Article  CAS  PubMed  Google Scholar 

  91. Rochtus A et al (2016) Genome-wide DNA methylation analysis of pseudohypoparathyroidism patients with GNAS imprinting defects. Clin Epigenetics 8:10

    Article  PubMed  PubMed Central  Google Scholar 

  92. Bastepe M, Lane AH, Jüppner H (2001) Paternal uniparental isodisomy of chromosome 20q—and the resulting changes in GNAS1 methylation—as a plausible cause of pseudohypoparathyroidism. Am J Hum Genet 68(5):1283–1289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Bastepe M et al (2011) Paternal uniparental isodisomy of the entire chromosome 20 as a molecular cause of pseudohypoparathyroidism type Ib (PHP-Ib). Bone 48(3):659–662

    Article  CAS  PubMed  Google Scholar 

  94. Fernández-Rebollo E et al (2011) New mechanisms involved in paternal 20q disomy associated with pseudohypoparathyroidism. Eur J Endocrinol 163(6):953–962

    Article  CAS  Google Scholar 

  95. Dixit A et al (2013) Pseudohypoparathyroidism type 1b due to paternal uniparental disomy of chromosome 20q. J Clin Endocrinol Metab 98(1):E103–E108

    Article  CAS  PubMed  Google Scholar 

  96. Takatani R et al (2015) Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B). Bone 79:15–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Bastepe M et al (2003) Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. J Clin Invest 112(8):1255–1263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Linglart A et al (2005) A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS. Am J Hum Genet 76(5):804–814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Elli FM et al (2014) Autosomal dominant pseudohypoparathyroidism type Ib: a novel inherited deletion ablating STX16 causes loss of imprinting at the A/B DMR. J Clin Endocrinol Metab 99(4):E724–E728

    Article  CAS  PubMed  Google Scholar 

  100. Richard N et al (2012) A new deletion ablating NESP55 causes loss of maternal imprint of A/B GNAS and autosomal dominant pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab 97(5):E863–E867

    Article  CAS  PubMed  Google Scholar 

  101. Bastepe M et al (2005) Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nat Genet 37(1):25–27

    CAS  PubMed  Google Scholar 

  102. Chillambhi S et al (2010) Deletion of the noncoding GNAS antisense transcript causes pseudohypoparathyroidism type Ib and biparental defects of GNAS methylation in cis. J Clin Endocrinol Metab 95(8):3993–4002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Linglart A, Bastepe M, Jüppner H (2007) Similar clinical and laboratory findings in patients with symptomatic autosomal dominant and sporadic pseudohypoparathyroidism type Ib despite different epigenetic changes at the GNAS locus. Clin Endocrinol (Oxf) 67(6):822–831

    Article  CAS  Google Scholar 

  104. Bréhin AC et al (2015) Loss of methylation at GNAS exon A/B is associated with increased intrauterine growth. J Clin Endocrinol Metab 100(4):E623–E631

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Richard N et al (2013) Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLalphas in fetal development. J Clin Endocrinol Metab 98(9):E1549–E1556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Thier 10, 50 Blossom Street, Boston, MA, 02114, USA

    O. Tafaj & H. Jüppner

  2. Pediatric Nephrology Unit, Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    H. Jüppner

Authors
  1. O. Tafaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. Jüppner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. Jüppner.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

For this review article no studies with human participants or animal experimentation were performed by the two authors.

Informed consent

For this type of study formal consent is not required.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tafaj, O., Jüppner, H. Pseudohypoparathyroidism: one gene, several syndromes. J Endocrinol Invest 40, 347–356 (2017). https://doi.org/10.1007/s40618-016-0588-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-016-0588-4

Keywords

Search

Navigation