Skip to main content
SpringerLink
Log in
Book cover

Growth Hormone Related Diseases and Therapy pp 3–16Cite as

Growth Hormone Receptor in Growth

  • Chapter
  • First Online:

  • 1105 Accesses

Part of the book series: Contemporary Endocrinology ((COE))

Abstract

It has been approximately 20 years since the cloning and characterization of the human growth hormone (GH) receptor, GHR, gene. Cell-surface GHR binds circulating GH, which promotes postnatal growth by regulating the expression of insulin-like growth factor (IGF)-I. Mutations in the GHR gene cause GH insensitivity (GHI) syndrome, also known as Laron syndrome, a syndrome characterized by severe postnatal growth retardation and low serum IGF-I concentrations in the presence of normal or elevated GH levels. Over 70 GHR mutations have been reported, with majority of the mutations found in exons encoding for the extracellular domain of the GHR. Inheritance of GHR mutations is predominantly autosomal recessive. Evaluating the impact of identified mutations on GHR structure and function is important to understand the pathophysiology of the disease. Therapeutic options for patients carrying mutations in the GHR gene have recently expanded to include recombinant IGF-I therapy.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Baker J, Liu JP, Robertson EJ, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 1993;75:73–82.

    PubMed  CAS  Google Scholar 

  2. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-I) and type I IGF receptor (Igflr). Cell. 1993;75:59–72.

    PubMed  CAS  Google Scholar 

  3. Woods KA, Camacho-Hubner C, Savage MO, Clark AJ. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. New Engl J Med. 1996;335:1363–7.

    Article  PubMed  CAS  Google Scholar 

  4. Walenkamp MJE, Karperien M, Pereira AM, et al. Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. J Clin Endocrinol Metab. 2005;90:2855–64.

    Article  PubMed  CAS  Google Scholar 

  5. Netchine I, Azzi S, Houang M, et al. Partial primary deficiency of insulin-like growth factor (IGF)-I activity associated with IGF-1 mutation demonstrates its critical role in growth and brain development. J Clin Endocrinol Metab. 2009;94(10):3913–21.

    Article  PubMed  CAS  Google Scholar 

  6. Saenger P, Czernichow P, Hughes I, Reiter EO. Small for gestional age: short stature and beyond. Endocr Rev. 2007;28(2):219–51.

    Article  PubMed  CAS  Google Scholar 

  7. Rosenfeld RG. Molecular mechanisms of IGF-I deficiency. Horm Res. 2006;65 Suppl 1:15–20.

    Article  PubMed  CAS  Google Scholar 

  8. Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J. Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr Rev. 1994;15(3):369–90.

    PubMed  CAS  Google Scholar 

  9. Rosenbloom AL. Physiology and disorders of the growth hormone receptor (GHR) and GH-GHR signal transduction. Endocrine. 2000;12(2):107–19.

    Article  PubMed  CAS  Google Scholar 

  10. Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary dwarfism with high serum concentation of growth hormone – a new inborn error of metabolism? Isr J Med Sci. 1966;2(2):152–5.

    PubMed  CAS  Google Scholar 

  11. Eshet R, Laron Z. Defects of human growth hormone receptors in the liver of two patients with Laron-type dwarfism. Isr J Med Sci. 1984;20:8–11.

    PubMed  CAS  Google Scholar 

  12. Leung DW, Spencer SA, Cachianes G, et al. Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature. 1987;330(6148):537–43.

    Article  PubMed  CAS  Google Scholar 

  13. Godowski PJ, Leung DW, Meacham LR, et al. Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type dwarfism. Proc Natl Acad Sci USA. 1989;86:8083–7.

    Article  PubMed  CAS  Google Scholar 

  14. Savage MO, Attie KM, David A, Metherell LA, Clark AJ, Camacho-Hubner C. Endocrine assessment, molecular characterization and treatment of growth hormone insensitivity disorders. Nat Clin Pract Endocrinol Metab. 2006;2:395–407.

    Article  PubMed  CAS  Google Scholar 

  15. Diniz ET, Jorge AA, Arnhold IJ, Rosenbloom AL, Bandeira F. Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome. Arq Bras Endocrinol Metab. 2008;52(8):1263–70.

    Article  Google Scholar 

  16. Brown RJ, Adams JJ, Pelekanos RA, et al. Model for growth hormone receptor activation based on subunit rotation within a receptor dimer. Nat Struct Mol Biol. 2005;12(9):814–21.

    Article  PubMed  CAS  Google Scholar 

  17. Flores-Morales A, Greenhalgh CJ, Norstedt G, Rico-Bautista E. Negative regulation of growth hormone receptor signaling. Mol Endocrinol. 2006;20(2):241–53.

    Article  PubMed  CAS  Google Scholar 

  18. Rosenfeld RG, Hwa V. The growth hormone cascade and its role in mammalian growth. Horm Res. 2009;71 Suppl 2:36–40.

    Article  PubMed  CAS  Google Scholar 

  19. Domene HM, Hwa V, Argente J, et al. Human acid-labile subunit deficiency: clinical, endocrine and metabolic consequences. Horm Res. 2009;72(3):129–41.

    Article  PubMed  CAS  Google Scholar 

  20. Ning Y, Schuller AG, Bradshaw S, et al. Diminished growth and enhanced glusoce metabolism in triple knockout mice containing mutations of the insulin-like growth factor binding protein-3, -4, and -5. Mol Endocrinol. 2006;20(9):2173–86.

    Article  PubMed  CAS  Google Scholar 

  21. Twigg SM, Baxter RC. Insulin-like growth factor binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit. J Biol Chem. 1998;273:6074–9.

    Article  PubMed  CAS  Google Scholar 

  22. Buckway CK, Guevara-Aguirre J, Pratt KL, Burren CP, Rosenfeld RG. The IGF-I generation test revisited: a marker of GH sensitivity. J Clin Endocrinol Metab. 2001;86(11):5176–83.

    Article  PubMed  CAS  Google Scholar 

  23. Chatterjee S, Pal JK. Role of 5′- and 3′-untranslated regions of mRNAs in human diseases. Biol Cell. 2009;101(5):251–62.

    Article  PubMed  CAS  Google Scholar 

  24. Gent J, van Kerkhof P, Roza M, Bu G, Strous GJ. Ligand-independent growth hormone receptor dimerization occurs in the endoplastic reticulum and is required for ubiquitin system-dependent endocytosis. Proc Natl Acad Sci USA. 2002;99(15):9858–63.

    Article  PubMed  CAS  Google Scholar 

  25. Ballesteros M, Leung K-C, Ross RMJ, Iismaa TP, Ho KKY. Dostribution and abundance of messenger ribonucleic acid for growth hormone receptor isoforms in human tissues. J Clin Endocrinol Metab. 2000;85(8):2865–71.

    Article  PubMed  CAS  Google Scholar 

  26. Dastot F, Sobrier M-L, Duquesnoy P, Duriez B, Goossens M, Amselem S. Alternative spliced forms in the cytoplasmic domain of the human growth hormone (GH) receptor regulate its ability to generate a soluble GH-binding protein. Proc Natl Acad Sci USA. 1996;93:10723–8.

    Article  PubMed  CAS  Google Scholar 

  27. Ross RJM, Esposito N, Shen XY, et al. A short isoform of the human growth hormone receptor functions as a dominant negative inhibitor of the full-length receptor and generates large amounts of binding protein. Mol Endocrinol. 1997;11:265–73.

    Article  PubMed  CAS  Google Scholar 

  28. Ayling RM, Ross R, Towner P, et al. A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nat Genet. 1997;16(1):13–4.

    Article  PubMed  CAS  Google Scholar 

  29. Iida K, Takahashi Y, Kaji H, et al. Growth hormone (GH) insensitivity syndrome with high serum GH-binding protein levels caused by a heterozygous splice site mutation of the GH receptor gene producing a lack of intracellular domain. J Clin Endocrinol Metab. 1998;83(2):531–7.

    Article  PubMed  CAS  Google Scholar 

  30. de Vos AM, Ultsch M, Kossiakoff AA. Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science. 1992;255:306–12.

    Article  PubMed  Google Scholar 

  31. Behncken SN, Waters MJ. Molecular recognition events involved in the activation of the growth hormone receptor by growth hormone. J Mol Recognit. 1999;12:355–62.

    Article  PubMed  CAS  Google Scholar 

  32. Amit T, Youdim MB, Hochberg Z. Clinical review 112: does serum growth hormone (GH) binding protein reflect human GH receptor function? J Clin Endocrinol Metab. 2000;85(3):927–32.

    Article  PubMed  CAS  Google Scholar 

  33. Fisker S. Physiology and pathophysiology of growth hormone-binding protein: methodological and clinical aspects. Growth Horm IGF Res. 2006;16:1–28.

    Article  PubMed  CAS  Google Scholar 

  34. Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG, Fielder PJ. The little women of Loja-growth hormone receptor deficiency in an inbred population of southern Ecuador. N Engl J Med. 1990;323(20):1367–74.

    Article  PubMed  CAS  Google Scholar 

  35. Berg MA, Guevara-Aguirre J, Rosenbloom AL, Rosenfeld RG, Francke U. Mutation creating a new splice site in the growth hormone receptro genes of 37 Ecuadorean patients with Laron syndrome. Hum Mutat. 1992;1:24–32.

    Article  PubMed  CAS  Google Scholar 

  36. Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG, Francke U. Growth hormone receptor deficiency in Ecuador. J Clin Endocrinol Metab. 1999;84:4436–43.

    Article  PubMed  CAS  Google Scholar 

  37. Fang P, Girgis R, Little BM, et al. Growth hormone (GH) insensitivity and insulin-like growth factor-I deficiency in Inuit subjects and in Ecuadorian cohort: functional stufied of two codon 180 GH receptor gene mutations. J Clin Endocrinol Metab. 2008;93:1030–7.

    Article  PubMed  CAS  Google Scholar 

  38. Berg MA, Peoples R, Pérez-Jurado L, et al. Receptor mutations and haplotypes in growth hormone receptor deficiency: a global survey and identification of the Ecuadorean D180splice mutation in an oriental Jewish patient. Acta Paediatr Scand Suppl. 1994;399:112–4.

    Article  CAS  Google Scholar 

  39. Jorge AA, Menezes Filho HC, Lins TS, et al. Founder effect of E180splice mutation in growth hormone receptor gene (GHR) identified in Brazilian patients with GH insensitivity. Arq Bras Endocrinol Metab. 2005;49(3):384–9.

    Article  Google Scholar 

  40. Espinosa C, Sjoberg M, Salazar T, et al. E180splice mutation in the growth hormone receptor gene in a Chilean family with growth hormone insensitivity: a probable common Mediterranean ancestor. J Pediatr Endocrinol Metab. 2008;21(12):1119–27.

    PubMed  CAS  Google Scholar 

  41. Duquesnoy P, Sobrier ML, Duriez B, et al. A single amino acid substitution in the exoplasmic domain of the human growth hormone (GH) receptor confers familial GH resistance (Laron syndrome) with positive GH-binding activity by abolishing receptor homodimerization. EMBO J. 1994;13(6):1386–95.

    PubMed  CAS  Google Scholar 

  42. Metherell LA, Akker SA, Munroe PB, et al. Pseudoexon activation as a novel mechanism for disease resulting in atypical growth-hormone insensitivity. Am J Hum Genet. 2001;69(3):641–6.

    Article  PubMed  CAS  Google Scholar 

  43. Fang P, Riedl S, Amselem S, et al. Primary growth hormone (GH) insensitivity insulin-like growth factor deficiency caused by novel compound heterozygous mutations of the GH receptor gene: genetic and functional studies of simple and compound heterozygous state. J Clin Endocrinol Metab. 2007;92(6):2223–31.

    Article  PubMed  CAS  Google Scholar 

  44. David A, Camacho-Hubner C, Bhangoo A, et al. An intronic growth hormone receptor mutation causing activation of a pseudoexon is associated with a broad spectrum of growth hormone insensitivity phenotypes. J Clin Endocrinol Metab. 2007;92(2):655–9.

    Article  PubMed  CAS  Google Scholar 

  45. Rieu M, Le Bouc Y, Villares SM, Postel-Vinay M-C. Familial short stature with very high levels of growth hormone binding protein. J Clin Endocrinol Metab. 1993;76(4):857–60.

    Article  PubMed  CAS  Google Scholar 

  46. Woods KA, Fraser NC, Postel-Vinay MC, Savage MO, Clark AJ. A homozygous splice site mutation affecting the intracellular domain of the growth hormone (GH) receptor resulting in Laron syndrome with elevated GH-binding protein. J Clin Endocrinol Metab. 1996;81(5):1686–90.

    Article  PubMed  CAS  Google Scholar 

  47. Silbergeld A, Dastot F, Klinger B, et al. Intronic mutation in the growth homone (GH) receptor gene from a girl with Laron syndrome and extremely high serum GH binding protein: extended phenotypic study in a very large pedigree. J Pediatr Endocrinol Metab. 1997;10:265–74.

    Article  PubMed  CAS  Google Scholar 

  48. Iida K, Takahashi Y, Kaji H, et al. Functional characterization of truncated growth hormone (GH) receptor- (1-277) causing partial GH insensitivity syndrome with high GH-binding protein. J Clin Endocrinol Metab. 1999;84(3):1011–6.

    Article  PubMed  CAS  Google Scholar 

  49. Aalbers AM, Chin D, Pratt KL, et al. Extreme elevation of serum growth hormone-binding protein concentrations resulting from a novel heterozygous splice site mutation of the growth hormone receptor gene. Horm Res. 2009;71:276–84.

    Article  PubMed  CAS  Google Scholar 

  50. David A, Miraki-Moud F, Shaw NJ, Savage MO, Clark AJ, Metherell LA. Identification and characterisation of a novel GHR defect disrupting the polypyrimidine tract and resulting in GH insensitivity. Eur J Endocrinol. 2010;162(1):37–42.

    Article  PubMed  CAS  Google Scholar 

  51. Goddard AD, Covello R, Luoh SM, et al. Mutations of the growth hormone receptor in children with idiopathis short stature. The Growth Hormone Insensitivity Study Group. N Engl J Med. 1995;333(17):1093–8.

    Article  PubMed  CAS  Google Scholar 

  52. Aisenberg J, Auyeung V, Pedro JF, et al. Atypical growth hormone insensitivity syndrome (GHIS) and severe insulin-like growth factor-I deficiency (IGFD) resulting from compound heterozygous mutations of the GH receptor (GHR), including a novel frameshift mutation affecting the intracellular domain. Horm Res Paediatr. 2010;74(6):406–11.

    Google Scholar 

  53. Strous GJ, Gent J. Dimerization, ubiquitylation and endocytosis go together in growth hormone receptor function. FEBS Lett. 2002;529:102–9.

    Article  PubMed  CAS  Google Scholar 

  54. Yamamoto H, Kouhara H, Iida K, Chihara K, Kasayama S. A novel growth hormone receptor gene deletion mutation in a patient with primary growth hormone insensitivity syndrome (Laron syndrome). Growth Horm IGF Res. 2008;18(2):136–42.

    Article  PubMed  CAS  Google Scholar 

  55. Kaji H, Nose O, Tajiri H, et al. Novel compound heterozygous mutations of growth hormone (GH) receptor gene in a patient with GH insensitivity syndrome. J Clin Endocrinol Metab. 1997;82(11):3705–9.

    Article  PubMed  CAS  Google Scholar 

  56. Gastier JM, Berg MA, Vesterhus P, Reiter EO, Francke U. Diverse deletions in the growth hormone receptor gene cause growth hormone insensitivity syndrome. Hum Mutat. 2000;16(4):323–33.

    Article  PubMed  CAS  Google Scholar 

  57. Milward A, Metherell L, Maamra M, et al. Growth hormone (GH) insensitivity syndrome due to a GH receptor truncated after Box1, resulting in isolated failure of STAT5 signal transduction. J Clin Endocrinol Metab. 2004;89:1259–66.

    Article  PubMed  CAS  Google Scholar 

  58. Tiulpakov A, Rubtsov P, Peterkova V, Bezlepkina O, Chrousos GP, Hochberg Z. A novel C-terminal growth hormone receptor (GHR) mutation results in impaired GHR-STAT5 but normal STAT3 signaling. J Clin Endocrinol Metab. 2005;90(1):542–7.

    Article  PubMed  CAS  Google Scholar 

  59. Kou K, Lajara R, Rotwein P. Amino acid substitutions in the intracellular part of the growth hormone receptor in a patient with the Laron syndrome. J Clin Endocrinol Metab. 1993;76(1):54–9.

    Article  PubMed  CAS  Google Scholar 

  60. Goddard AD, Dowd P, Chernausek S, et al. Partial growth-hormone insensitivity: the role of growth-hormone receptor mutations in idiopathic short stature. J Pediatr. 1997;131:S51–5.

    Article  PubMed  CAS  Google Scholar 

  61. Baumbach L, Schiavi A, Bartlett R, et al. Clinical, biochemical, and molecular investigations of a genetic isolate of growth hormone insensitivity (Laron’s syndrome). J Clin Endocrinol Metab. 1997;82(2):444–51.

    Article  PubMed  CAS  Google Scholar 

  62. Iida K, Takahashi Y, Kaji H, et al. The C422F mutation of the growth hormone receptor gene is not responsible for short stature. J Clin Endocrinol Metab. 1999;84(11):4214–9.

    Article  PubMed  CAS  Google Scholar 

  63. Chujo S, Kaji H, Takahashi Y, Okimura Y, Abe H, Chihara K. No correlation of growth hormone receptor gene mutation P561T with body height. Eur J Endocrinol. 1996;134(5):560–2.

    Article  PubMed  CAS  Google Scholar 

  64. Tomoyasu Y, Yamaguchi T, Tajima A, Nakajima T, Inoue I, Maki K. Further evidence for an association between mandibular height and the growth hormone receptor gene in a Japanese population. Am J Orthod Dentofacial Orthop. 2009;136(4):536–41.

    Article  PubMed  Google Scholar 

  65. Kang EH, Yamaguchi T, Tajima A, et al. Association of the growth hormone receptor gene polymorphisms with mandibular height in a Korean population. Arch Oral Biol. 2009;54(6):556–62.

    Article  PubMed  CAS  Google Scholar 

  66. Derr MA, Fang P, Sinha SK, Ten S, Hwa V, Rosenfeld RG. A novel Y332C missense mutation in the intracellular domain of the human growth hormone receptor does not alter STAT5b signaling: redundancy of GHR intracellular tyrosines involved in STAT5b signaling. Horm Res Paediatr. 2011;75(3):187–99.

    Google Scholar 

  67. Dos Santos C, Essioux L, Teinturier C, Tauber M, Goffin V, Bougneres P. A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat Genet. 2004;36:720–4.

    Article  PubMed  Google Scholar 

  68. Wassenaar MJ, Dekkers OM, Pereira AM, et al. Impact of the exon 3-deleted growth hormone (GH) receptor polymorphism on baseline height and the growth response to recombinant human GH therapy in GH-deficient (GFD) and non-GHD children with short stature: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2009;94(10):3721–30.

    Article  PubMed  CAS  Google Scholar 

  69. Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE, Group GISC. Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. J Clin Endocrinol Metab. 2007;92:902–10.

    Article  PubMed  CAS  Google Scholar 

  70. Bright GM, Mendoza JR, Rosenfeld RG. Recombinant human insulin-like growth factor-1 treatment: ready for primetime. Endocrinol Metab Clin North Am. 2009;38(3):625–38.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239-3098, USA

    Vivian Hwa

Authors
  1. Vivian Hwa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vivian Hwa .

Editor information

Editors and Affiliations

  1. Princess Alexandra Hospital &, The University of Queensland, Centres for Health Research, Ipswich Road Woolloongabba 199, Brisbane, 4102, Queensland, Australia

    Ken Ho

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Hwa, V. (2011). Growth Hormone Receptor in Growth. In: Ho, K. (eds) Growth Hormone Related Diseases and Therapy. Contemporary Endocrinology. Humana Press. https://doi.org/10.1007/978-1-60761-317-6_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-317-6_1

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60761-316-9

  • Online ISBN: 978-1-60761-317-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation