A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone

Santos, Christine Dos; Essioux, Laurent; Teinturier, Cécile; Tauber, Maïté; Goffin, Vincent; Bougnères, Pierre

doi:10.1038/ng1379

Cited by 303 publications

(377 citation statements)

References 18 publications

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“…47,48 This latter polymorphism was not found to be significantly more frequent in pygmies than in non-pygmies.…”

Section: Resultsmentioning

confidence: 68%

The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature

Becker¹,

Verdu²,

Georges³

et al. 2012

Eur J Hum Genet

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African pygmies are at the lower extreme of human variation in adult stature and many evolutionary hypotheses have been proposed to explain this phenotype. We showed in a recent study that the difference in average stature of about 10 cm observed between contemporary pygmies and neighboring non-pygmies has a genetic component. Nevertheless, the genetic basis of African pygmies' short stature remains unknown. Using a candidate-gene approach, we show that intronic polymorphisms in GH receptor (GHR) and insulin-like growth factor 1 (IGF1) genes present outlying values of the genetic distance between Baka pygmies and their non-pygmy Nzimé neighbors. We further show that GHR and IGF1 genes have experienced divergent natural selection pressures between pygmies and non-pygmies throughout evolution. In addition, these SNPs are associated with stature in a sample composed of 60 pygmies and 30 non-pygmies and this association remains significant when correcting for population structure for the GHR locus. We conclude that the GHR and IGF1 genes may have a role in African pygmies' short stature. The use of phenotypically contrasted populations is a promising strategy to identify new variants associated with complex traits in humans.

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“…47,48 This latter polymorphism was not found to be significantly more frequent in pygmies than in non-pygmies.…”

Section: Resultsmentioning

confidence: 68%

The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature

Becker¹,

Verdu²,

Georges³

et al. 2012

Eur J Hum Genet

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“…This hypothesis could explain why severe GHD subjects might present a rhGH dose-dependent GHR genotype-related effect on growth response with an apparent plateau at around 26 μg/kg/day (16 IU/m 2 / week), whereas this effect disappears with higher rhGH doses that lie further up on the dose-response curve for this condition. Similarly, SGA children treated with higher doses of rhGH showed no difference in growth response according to the GHR exon-3 genotype in contrast to SGA children treated with lower doses [40,41]. Duration of GH treatment also seems to play a major role in defining the sensitivity to the GHR genotype, in addition to the etiology of the short stature and its severity.…”

Section: Polymorphism Of the Ghrmentioning

confidence: 90%

“…While the latter two are classical single nucleotide polymorphisms, the polymorphism in exon 3 is an unusual one, leading to retention (full-length, fl; GHRfl) or deletion of exon 3 (d3; GHRd3), which encodes a 22-amino-acid residue sequence in the extracellular domain [37,38]. GHRd3 has recently been associated with the degree of height increase in response to GH replacement in children born short for gestational age (SGA), in those with ISS, and in a GHD population [39,40]. Patients with at least one GHRd3 allele (GHRfl/GHRd3; GHRd3/GHRd3) had a significantly better first year response leading to an improved adult height on rhGH treatment than patients with homozygosity for GHRfl [39].…”

Section: Polymorphism Of the Ghrmentioning

confidence: 99%

“…In the first report, for instance, Dos Santos et al [40] studied patients with either SGA or ISS so that in effect patients with normal GH secretion were treated with supraphysiological rhGH doses. Besides the various conditions studied it is also possible that the differences between the studies reported so far represent the problems of sample size.…”

Section: Polymorphism Of the Ghrmentioning

confidence: 99%

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Biological Determinants of Responsiveness to Growth Hormone: Pharmacogenomics and Personalized Medicine

Mullis¹

2010

Current Indications for Growth Hormone Therapy

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It is becoming most clear that many genes are involved in controlling the regulation of growth. Ultimately however, at the level of growth hormone (GH), the relevant question may be not whether a patient is GH-deficient, but whether he is GH-responsive. As these disturbances can be divided into two gross categories, namely alterations causing subnormal GH secretion and/or those presenting with subnormal GH sensitivity/responsiveness, the main aim of this review is to focus on genes involved in growth regulation leading to short stature caused by an alteration of GH insensitivity/GH responsiveness; in other words, clinical circumstances where individually adapted GH replacement therapy may help to increase height velocity and eventually final height.

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“…Moreover, when modeled by crystallography, the amino acids encoded by exon 3 of the GHR gene do not appear to interact in a significant manner with GH (16). In 2004, Dos Santos et al (17) transfected 293 HEK fibroblasts with vectors expressing both GHR isoforms, either alone or simultaneously, and quantified signal transduction by induction of the firefly luciferace gene coupled to the GH-responsive STAT5 promoter. They showed that transduction of GH signaling was approximately 30% greater through d3-GHR homo-and heterodimers than through fl-GHR homodimers.…”

Section: Functional Consequences Of the Ghr Exon 3 Deletion (D3-ghr)mentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Clinical and pharmacogenetic aspects of the growth hormone receptor polymorphism

Boguszewski

Barbosa

Svensson

et al. 2017

European Journal of Endocrinology

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Pharmacogenetics aims to maximize the beneficial effects of a medical therapy by identifying genetic finger prints from responders and non-responders and, thereby improving safety and efficacy profile of the drug. Most subjects who are deficient in growth hormone (GHD) are candidates for recombinant human GH (rhGH) therapy. To date, it is well established that even after adjustments for several clinical variables, such as age, gender, body composition and the age at onset of the GHD, response to rhGH treatment is highly variable among individuals, part of which is believed to be due to genetic factors within the GH system. As the first genetic variant to potentially influence the individual response to rhGH therapy in children with growth disorders, polymorphism in the GH receptor (GHR) has attracted a great interest as a target for pharmacogenetics. Studies have been conducted to compare the functional and molecular effects of the full-length GHR (fl-GHR) isoform with the exon 3 deleted (d3-GHR) isoform in children and adults treated with rhGH therapy. Additionally, the impact of the GHR polymorphism has been investigated in relation to the clinical status and response to medical treatment in acromegaly, especially to the GHR antagonist drug pegvisomant. We have performed a narrative review of the studies performed to date on the association of GHR polymorphism with rhGH response in children and adults, and its potential influence in the medical management of acromegaly. In addition, data from studies on the general population and in other chronic diseases examining a role of this genetic variant in the regulation of growth and metabolism are summarized. The growth hormone receptor (GHR)Growth hormone (GH) exerts its biological effects by binding to the GH receptor (GHR). The GHR protein is positioned at the cell membrane of almost every cell in the human body and contains a 246 amino acids long extracellular (GH-binding) domain, a transmembrane domain and a 350 amino acids long intracellular (cytoplasmic) domain. In total, the GHR protein is composed of 638 residues (1). Binding of GH to the GHR induces a series of subtle conformational events within a receptor homodimer, rather than a simple receptor dimerization, promoting a realignment of the two receptors both by relative rotation and by closer apposition just above the cell membrane (2). The parallel receptor transmembrane domains are converted into a rotated crossover orientation and the lower parts of the transmembrane helices are separated. GHR activation

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A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone

Cited by 303 publications

References 18 publications

The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature

The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature

Biological Determinants of Responsiveness to Growth Hormone: Pharmacogenomics and Personalized Medicine

MECHANISMS IN ENDOCRINOLOGY: Clinical and pharmacogenetic aspects of the growth hormone receptor polymorphism

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