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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 2 435-437
Copyright © 1997 by The Endocrine Society

Experimental Studies

Nine Novel Growth Hormone Receptor Gene Mutations in Patients with Laron Syndrome1

Marie-Laure Sobrier, Florence Dastot2, Philippe Duquesnoy, Nurgün Kandemir, Nursen Yordam, Michel Goossens and Serge Amselem

Laboratoire de Génétique Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U91 (M-L.S., F.D., P.D., M.G., S.A.), Hôpital Henri Mondor, 94010 Créteil, France; and Hacettepe University, Division of Pediatric Endocrinology (N.K., N.Y.), Ankara, Turkey

Address all correspondence and requests for reprints to: Marie-Laure Sobrier, Laboratoire de Génétique Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U91, Hôpital Henri Mondor, 51 Av. du Marechal de Lattre de Tassigny, 94010 Créteil, France.


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
The GH receptor (GHR) is a member of the cytokine receptor superfamily; GH binding protein is the solubilized extracellular domain of the GHR. Abnormalities in the GHR produce an autosomal recessive form of GH resistance, the Laron syndrome, characterized by growth failure and the clinical appearance of severe GH deficiency despite elevated circulating GH levels. In 13 unrelated patients with undetectable levels of GH binding protein, we characterized nine novel mutations in the GHR gene. These molecular defects comprise three nonsense mutations (Q65X, W80X, and W157X), one frameshift (36delC), two splice defects (G->A at 70+1, C->T at 723), and three missense mutations (C38S, S40L, and W50R) located in the extracellular domain of the receptor, and thus would be expected to interfere with GH binding activity. These results further confirm the broad heterogeneity of mutations underlying this rare GH resistance syndrome.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
GH BINDS specifically to a transmembrane receptor (GHR), thereby stimulating body growth, regulating several metabolic processes, including insulin and anti-insulin-like effects on adipocytes, and stimulating muscle cell and erythroid progenitor cell proliferation (1). The GHR gene spans 87 kilobases and includes nine coding exons (2). Several additional exons, which are located in the 5' untranslated region (3), are probably involved in specific-stage or in tissue-regulated expression. This receptor is expressed mainly in the liver but in a variety of other tissues as well. It is a 620-amino acid transmembrane protein consisting of an extracellular domain that includes the GH binding sites, a single transmembrane domain, and a cytoplasmic domain (4). Dimerization of the GHR, which occurs around one molecule of GH, has been shown to be essential to receptor activation (5). GHR is a member of a superfamily of cell surface receptors for a variety of cytokines, hemopoietic growth factors, and hormones (6).

A soluble form, GH binding protein (GHBP), circulates in plasma and corresponds to the extracellular domain of the receptor. This high-affinity serum GHBP could be involved in the control of circulating GH levels (7). A lack of plasma GH binding activity has been found in the majority of patients with Laron syndrome (LS), a GH insensitivity condition due, in most cases, to GH receptor deficiency (8). This rare autosomal recessive disorder is characterized by a clinical appearance of severe GH deficiency with high level of circulating GH, in contrast to low serum insulin-like growth factor (IGF)-I values, which do not rise upon administration of GH (9). A variety of GHR mutations has been shown to cause LS. They mainly affect the extracellular domain of the molecule and include deletion of several exons (2) and several missense, nonsense, frameshift, and splice defects (10, 11, 12, 13, 14, 15). In patients with LS and positive GHBP, GH resistance can result from a postreceptor defect (16, 17), or a GHR point mutation impairing either the homodimerization step (18) or the maturation of primary GHR transcripts leading to a receptor without transmembrane and intracellular domains (19).

In this study, we analyzed the GHR gene from 13 unrelated patients of different ethnic origins with LS caused by GHR deficiency.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Patients

DNA was obtained from members of families in which one or two subjects were affected. Phenotype classification was done according to current criteria (20). Plasma GH binding activity was undetectable in all the patients except one (No. 8), in whom values were unknown. Gross DNA rearrangements at the GHR locus were ruled out by means of Southern blot analysis as described elsewhere (21).

Denaturing gradient gel electrophoresis (DGGE) of PCR-amplified products and DNA sequencing

Genomic DNA (1 µg) extracted from peripheral blood cells was used as template in a PCR reaction. PCR parameters were 1 min denaturation (94 C), 1 min annealing (55 C), and 2 min polymerization (72 C) for 40 cycles. Exons 2 to 9 and the surrounding intronic sequences (except for the 3' end of intron 2) were analyzed by means of DGGE as described (13). The sequence of DNA samples showing a shift in mobility in DGGE was determined after asymmetric amplification (22). Exon 10 was analyzed by direct sequencing.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
In 13 unrelated patients with LS, screening of the nine coding exons of the GH receptor gene led to the description of nine novel mutations.

The molecular results are summarized in Table 1Go. Five mutations were located in exon 4 and consisted of one nonsense mutation (Q65X), three missense mutations (C38S, S40L, and W50R), and a frameshift (36delC). The latter defect is predicted to create a premature termination signal at codon 62. Patient No. 2, who carried the W50R mutation, also had a stop mutation (W80X) located on exon 5. These two mutations were on separate GHR alleles, as determined by cloning and sequencing GHR transcripts obtained from circulating lymphocytes (data not shown).


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  		Table 1. Summary of new GHR mutations

 
The W157X nonsense mutation, which is located in the middle of exon 6 (patient No. 3), was present in the homozygous state.

In exon 7, a nucleotide change (C->T at 723) was identified in patient No. 7. This mutation, which did not change the genetic code, is likely to interfere with GHR messenger RNA splicing because it potentially creates a new donor splice site, as discussed below.

The same intronic mutation was identified in two unrelated families (patients Nos. 5 and 6), affecting four individuals (two in each family) involving one of the invariant nucleotides in intron 2 (G->A at 70+1).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
This survey of 13 unrelated patients of various ethnic origins with LS caused by GHR deficiency led to the discovery of nine novel mutations in the GHR gene. The other four mutations found in this study have been described previously (R43X in exon 4, V125A in exon 5, and R217X and del XAT at nucleotides 743–744 in exon 7) (11, 13, 14). As expected in such a rare recessively inherited disease, most of the patients were homozygous as a result of consanguineous unions that were sometimes unrecognized (families Nos. 1, 3, and 4). All the patients had different GHR mutations except for those belonging to families Nos. 5 and 6. However, these two consanguineous families have the same ethnic background, suggesting a common origin of this mutation (i.e. a founder effect).

Most of the splice mutations so far characterized in patients with LS are located in the donor or acceptor consensus splice sequences. This is the case for the splice mutation identified in the four patients belonging to families No. 5 and 6. This substitution modifies the first nucleotide of intron 2 and is therefore expected to impair splicing (23). In patient No. 7, in whom the whole GHR gene sequence was screened, the only modification found (a C->T transition at position 723) does not change the genetic code. Nevertheless, examination of the surrounding sequence points to a putative cryptic donor splice site: the mutated sequence [Ggtgagt] matches the 5' splice consensus sequence [Ggta/gagt] (24). This mutation should therefore result in the deletion of 63 nucleotides from the messenger RNA and 21 amino acids in the carboxy terminal end of the extracellular domain of the GH receptor. This defect is reminiscent of the mutation identified in Ecuadorean patients with LS (12), and that in exon 7 reported in a Bahamian genetic isolate (25).

All the new missense mutations described in this study affect residues involved in the edification of the GH binding site (Fig. 1Go), as predicted by the three-dimensional model of the extracellular domain (cysteine, serine, and tryptophan at positions 38, 40, and 50, respectively) (26). Although in vitro expression studies are required to determine the functional consequences of each of these substitutions, it is striking that they involve residues that are highly conserved through evolution among the members of the cytokine receptor superfamily (6). The cysteine at position 38, which is involved in a covalent bond, is indeed a key element of secondary structure. The tryptophan at position 50 is part of the core of the barrels (26), whereas the serine at position 40 is related to a peptide fragment that belongs to the GH binding site I.



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  		Figure 1. Three-dimensional carbon-{alpha} trace of the human GH-GHBP complex showing position of missense mutations. Hormone (black) is bound to two molecules of extracellular domain of its receptor (gray). Position of mutated residues is depicted in black in both GHBP molecules. The figure was produced from deposited crystallographic coordinates (26).

 
With this report, a total of 28 different GHR gene mutations have been described in individuals with LS (8). They include a deletion of exons, seven nonsense mutations, three frameshifts, seven splice defects, and ten missense mutations. Interestingly, the great majority of these mutations is located in the extracellular domain of the receptor, the main target being exon 4, which is mutated in at least 25% of patients with LS. This exon should be the first GHR gene fragment to be screened for mutations.


   Acknowledgments
 
The authors thank Dr. Juif (France), Dr. Savage (England), Dr. Wollmann (Germany), Dr. Krzisnick (Slovenia), and Dr. Pintos (Spain) for identifying patients, and Pharmacia and Upjohn for their assistance in obtaining blood samples for genotype analysis.


   Footnotes
 
1 This work was supported by the Institut National de la Santé et de la Recherche Médicale and by grants from the Assistance Publique Hôpitaux de Paris (CRC) and the Association Française contre les Myopathies (MG). Back

2 Recipient of a fellowship from the Ministere de la Recherche et de la Technologie. Back

Received June 13, 1996.

Revised September 23, 1996.

Revised October 3, 1996.

Accepted October 15, 1996.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Isaksson OGP, Eden S, Jansson J-O. 1985 Mode of action of pituitary growth hormone on target cells. Annu Rev Physiol. 47:483–499.[CrossRef][Medline]
  2. Godowski PJ, Leung DW, Meacham LR, et al. 1989 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. 86:8083–8087.[Abstract/Free Full Text]
  3. Pekhletsky RI, Chernov BK, Rubtsov PM. 1992 Variants of the 5'-untranslated sequence of human growth hormone receptor mRNA. Mol Cell Endocrinol. 90:103–109.[CrossRef][Medline]
  4. Leung DW, Spencer SA, Cachianes G, et al. 1987 Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature. 330:537–543.[CrossRef][Medline]
  5. Carter-Su C, Schwartz J, Smit LS. 1996 Molecular mechanism of growth hormone action. Annu Rev Physiol. 58:187–207.[CrossRef][Medline]
  6. Wells JA, De Vos AM. 1996 Hematopoitic receptor complexes. Annu Rev Biochem. 65:609–634.[CrossRef][Medline]
  7. Veldhuis J, Johnson M, Faunt L, Mercado M, Baumann G. 1993 Influence of the high affinity growth hormone (GH)-binding protein on plasma profiles of free and bound GH and on apparent half-life of GH. J Clin Invest. 91:629–641.
  8. Amselem S, Sobrier M-L, Dastot F, Duquesnoy P, Duriez B, Goossens M. 1996 Molecular basis of inherited growth hormone resistance in childhood. In: Ross RJM, Savage MO, eds. Clinical endocrinology and metabolism. Growth hormone resistance 10(3). London: Bailliere’s; 353–370.
  9. Laron Z, Pertzelan A, Karp M, Kowadlo-Silbergeld A, Daughaday WH. 1971 Administration of growth hormone to patients with familial dwarfism with high plasma immunoreactive growth hormone: measurement of sulfation factor, metabolic and linear growth response. J Clin Endocrinol Metab. 33:332–342.[Medline]
  10. Amselem S, Duquesnoy P, Attree O, et al. 1989 Laron dwarfism and mutations of the growth hormone-receptor gene. N Engl J Med. 321:989–995.[Abstract]
  11. Amselem S, Sobrier M-L, Duquesnoy P, et al. 1991 Recurrent nonsense mutations in the growth hormone receptor from patients with Laron dwarfism. J Clin Invest. 87:1098–1102.
  12. Berg MA, Guevara-Aguirre J, Rosenbloom AL, Rosenfeld RG, Franke U. 1992 Mutation creating a new splice site in the growth hormone receptor genes of 37 Ecuadorean patients with Laron syndrome. Human Mutation. 1:24–34.[CrossRef][Medline]
  13. Amselem S, Duquesnoy P, Duriez B, et al. 1993 Spectrum of growth hormone receptor mutations and associated haplotypes in Laron syndrome. Hum Mol Genet. 2:355–359.[Abstract/Free Full Text]
  14. Berg M, Argente J, Chernausek S, et al. 1993 Diverse growth hormone receptor gene mutations in Laron syndrome. Am J Hum Genet. 52:998–1005.[Medline]
  15. Berg MA, Peoples R, Perez-Jurado L, et al. 1994 Receptor mutations and haplotypes in growth hormone receptor deficiency: a global survey and identification of the Ecuadorean E180splice mutation in an oriental Jewish patient. Acta Paediatr. 83:112–114.
  16. Laron Z, Klinger B, Eshet R, Kaneti H, Karasik A, Silbergeld A. 1993 Laron syndrome due to a post-receptor defect: response to IGF-I treatment. Isr J Med Sci. 29:757–763.[Medline]
  17. Woods K, Camacho-Hübner C, Clark A, Savage M. Homozygous partial IGF-1 gene deletion in a patient with intrauterine growth retardation and postnatal growth failure. Program of 35th Annual Meeting of the European Society Pediatric Endocrinology, 1996, Montpelier, France, (Abstract 22).
  18. Duquesnoy P, Sobrier ML, Duriez B, et al. 1994 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. 13:1386–1395.[Medline]
  19. Woods KA, Fraser NC, Postel-Vinay M-C, Savage MO, Clark AJL. 1996 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. 81:1686–90.[Abstract]
  20. Blum WF, Cotterill AM, Postel-Vinay MC, et al. 1994 Improvement of diagnostic criteria in growth hormone insensitivity syndrome: solutions and pitfalls. Acta Paediatr. 83:117–124.[Medline]
  21. Meacham LR, Brown MR, Murphy TL, et al. 1993 Characterization of a noncontiguous gene deletion of the growth hormone receptor in Laron’s syndrome. J Clin Endocrinol Metab. 77:1379–1383.[Abstract]
  22. Gyllensten UB, Erlich HA. 1988 Generation of single-strand DNA by the polymerase chain reaction and its application to direct sequencing of HLA-DQA locus. Proc Natl Acad Sci USA. 85:7652–7656.[Abstract/Free Full Text]
  23. Krawczak M, Reiss J, Cooper DN. 1992 The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet. 90:41–54.[Medline]
  24. Ohshima Y, Gotoh Y. 1987 Signals for the selection of a splice site in pre-mRNA-computer analysis of splice junction sequences and like sequences. J Mol Biol. 195:247–259.[CrossRef][Medline]
  25. Schiavi A, Bartlett R, Brown M, et al. 1995 Preferential transcription from an activated cryptic splice site results in aberrant mRNA processing and protein truncation in a Bahamian genetic isolate of Laron syndrome. The University of Chicago Press, Annual Meeting of the American Society of Human Genetics, Minneapolis, 1995, p 227 (Abstract).
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