Other entities represented in this entry:
HGNC Approved Gene Symbol: GHR
SNOMEDCT: 38196001; ICD10CM: E34.321;
Cytogenetic location: 5p13.1-p12 Genomic coordinates (GRCh38): 5:42,423,439-42,721,878 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p13.1-p12 | {Hypercholesterolemia, familial, modifier of} | 143890 | Autosomal dominant; Autosomal recessive | 3 |
| Growth hormone insensitivity, partial | 604271 | Autosomal dominant | 3 | |
| Increased responsiveness to growth hormone | 604271 | Autosomal dominant | 3 | |
| Laron dwarfism | 262500 | Autosomal recessive | 3 |
Biologically active growth hormone (GH1; 139250) binds its transmembrane receptor (GHR), which dimerizes to activate an intracellular signal transduction pathway leading to synthesis and secretion of insulin-like growth factor I (IGF1; 147440). In plasma, IGF1 binds to the soluble IGF1 receptor (IGF1R; 147370). At target cells, this complex activates signal-transduction pathways that result in the mitogenic and anabolic responses that lead to growth.
Godowski et al. (1989) reported that the GHR gene has 9 exons that encode the receptor and several additional exons in the 5-prime untranslated region. The coding exons span at least 87 kb.
GHR consists of an extracellular domain of 246 amino acids, a single transmembrane domain, and a cytoplasmic domain. Exons 3 to 7 encode the extracellular domain. There are 2 isoforms of GHR in humans, generated by retention or exclusion of exon 3 during splicing: a full-length isoform and an isoform that lacks exon 3 (d3GHR). The generation of 2 transcripts that differ by the skipping of a coding exon results from homologous recombination, which mimics alternative splicing between the 2 retroviral sequences that flank the skipped exon (Pantel et al., 2000). The allele encoding d3GHR is specific to humans. Results of the studies of Pantel et al. (2003) supported the hypothesis that the d3GHR isoform is transcribed from a GHR allele carrying a genomic deletion of exon 3 rather than by alternative splicing; see 600946.0031.
Two isoforms of GHR, which differ in the presence or absence of sequence encoded by exon 3, are expressed in the placenta and appeared to be due to alternative splicing. Specifically, 3 expression patterns were observed: full length only, short only (missing exon 3), or an approximately 1:1 combination of the 2 isoforms. Stallings-Mann et al. (1996) found no change in the expression of the short form when placentas from different stages of gestation were examined, suggesting that splicing was not developmentally regulated. However, when isoform expression patterns were examined in each component of a given placenta, it was evident that alternative splicing of exon 3 is individual-specific. Surprisingly, this appears to be the result of a polymorphism in the GHR gene. Stallings-Mann et al. (1996) analyzed the expression of the full-length and short forms in Hutterite pedigrees and found results consistent with simple mendelian inheritance of 2 differing alleles in which exon 3 is spliced in an 'all or none' fashion. They concluded that the alternative splicing of exon 3 in GHR transcripts is the result of an unusual polymorphism that significantly alters splicing of the transcript, and that the relatively high frequency (approximately 10%) of homozygosity for the allele producing transcripts lacking exon 3 suggests the possibility that it may play a role in polygenically determined events, i.e., may have a selective advantage under some circumstances. A genetic polymorphism resulting in deletion of an entire exon from an mRNA without compromising structure or function of the resultant protein is unusual. Stallings-Mann et al. (1996) noted that exon 3 encodes a segment of the extracellular domain that is 22 amino acids long, and its removal results in the substitution of an aspartic acid for the alanine residue at the junction of exons 2 and 4. Exon 3 is not highly conserved among GHRs, and a homolog does not exist in the closely related prolactin receptor (176761). Placentas showing homozygosity for the deletion were obtained from women who gave birth to apparently normal children.
Amit et al. (1997) studied a new human GHR mRNA species that encodes a smaller isoform, termed GHRtr. This mRNA is expressed in several human tissues and predicts a truncated GHR protein that lacks 97.5% of the intracellular domain. Because GHR and GHRtr, which display similar binding affinities, are coexpressed in several tissues, Amit et al. (1997) hypothesized that they may interrelate. To compare the biologic properties of GHRtr and GHR, they used Chinese hamster ovary (CHO) cell lines that stably expressed each isoform. Crosslinking of radiolabeled GH to CHO/GHRtr cells resulted in a major specific complex with an apparent molecular mass of approximately 100 kD, indicating that GHRtr is approximately 80 kD. Compared to CHO/GHR cells, CHO/GHRtr cells secreted higher amounts of soluble GHBP and had a markedly reduced ability to internalize GH. Unlike CHO/GHR cells, CHO/GHRtr cells did not exhibit GH-induced receptor downregulation. Analysis of the constitutive turnover of cellular GHR and soluble GHBP showed that incubation of CHO/GHR cells with cycloheximide caused a parallel disappearance of hGHR and GHBP. In contrast, GHRtr showed no decline after cycloheximide treatment of CHO/GHRtr cells, suggesting that the bulk of GHRtr and GHBP may be derived from preformed proteins. Thus, the results indicate that, unlike GHR, GHRtr is fixed at the cell membrane: it undergoes minimal internalization, it is not downregulated by hGH, and it has no constitutive turnover. GHRtr does have increased capacity to generate soluble GHBP; since it failed to undergo ligand-induced internalization, the source of the continuous, undisturbed GHBP release into the medium may be an intracellular storage pool. The authors concluded that the relative abundance of the GHR and GHRtr isoforms, determined through regulation of splicing, could be of critical importance in modulating the biologic effects of GH.
Menon et al. (1997) studied binding of a 42-bp enhancer element in the promoter of the L1 transcript of the murine GHR to nuclear proteins specific for the coding strand or the DNA duplex. Using methylation interference footprinting and electromobility shift assays with mutant oligonucleotides, the DNA-binding sites for the single-strand DNA-binding protein and the double-strand DNA-binding protein were mapped and shown to be contiguous with partial overlap. Southwestern analysis indicated that a protein of molecular mass 23 kD exhibited binding activity specific to the coding strand of the enhancer element. Menon et al. (1997) concluded that single-strand and double-strand DNA-binding proteins conjointly regulate the expression of the murine GHR gene.
In cirrhosis, there is a state of acquired GH resistance, as defined by high circulating GH levels with low IGF1 levels. Patients with end-stage liver failure respond, however, to supraphysiologic doses of GH with an increase in circulating IGF1 levels. Shen et al. (1998) analyzed GHR expression in cirrhotic liver from 17 patients with end-stage liver disease. Specific binding of labeled GH was identified in all cirrhotic livers studied, and the binding affinity for the GHR was similar in cirrhotic and normal livers. The amount of GH binding per mg of liver membrane protein was variable in both normal and cirrhotic liver, although it was generally lower in cirrhotic liver. GHR expression was identified in cirrhotic liver by Northern blot analysis, RT-PCR, and ribonuclease protection assays. On Northern blot analysis, a single transcript of 4.8 kb was identified in normal and cirrhotic tissues, but RT-PCR identified both full-length GHR and truncated forms of the GHR; this result was confirmed by ribonuclease protection assays. The authors concluded that the low level of GHR in cirrhotic liver may contribute to the acquired GH resistance found in cirrhotic patients, and that the reduced expression of both full-length and truncated GHR is compatible with the reduced levels of GH-binding protein found in cirrhosis, as this truncated receptor has previously been reported to generate large amounts of GHBP. They suggested that the demonstration of GH binding to cirrhotic liver explains why these patients with GH resistance may still respond to supraphysiologic doses of GH.
Shuto et al. (1999) reported a case of acquired GH resistance in a severely malnourished 87-year-old man and concluded that decreased expression of GHR mRNA in the liver, possibly caused by malnutrition, may have been responsible for the GH resistance.
Ballesteros et al. (2000) developed quantitative RT-PCR assays specific for full-length and truncated GHRs and investigated their expression in various human tissues and cell lines. Full-length GHR and truncated GHR(1-279) mRNAs were readily detectable in all tissues investigated, with liver, fat, muscle, and kidney showing high levels of expression. These 2 receptor isoforms were also detected in a range of human cell lines, with strongest expression in the lymphoblastoid cell line IM9. In contrast, truncated GHR(1-277) mRNA was expressed at low levels in liver, fat, muscle, kidney, and prostate and in trace amount in IM9 cells. Full-length GHR was the most abundant isoform, accounting for over 90% of total receptor transcripts in liver, fat, and muscle for quantitative RT-PCR. However, liver had 2- to 4-fold more full-length receptor mRNA and 16- to 40-fold more GHR(1-277) mRNA than fat and muscle, whereas the mRNA levels of GHR(1-279) were similar in the 3 tissues. GHR(1-279) constituted less than 4% in liver and 7 to 10% in fat and muscle. GHR(1-277) accounted for 0.5% of total GHR transcripts in liver and less than 0.1% in the other 2 tissues. The authors concluded that the absolute and relative abundance of mRNA of the 3 GHR isoforms may be tissue-specific and that regulation of expression of exon 9 alternatively spliced GHR variants may provide a potential mechanism for modulation of GH sensitivity at the tissue level.
Leung et al. (2000) investigated insulin regulation of total, intracellular, and cell surface GHRs and receptor biosynthesis and turnover in a human hepatoma cell line with differentiated phenotype (HuH7). Insulin upregulated total and intracellular GHRs in a concentration-dependent manner. It increased surface GHRs in a biphasic manner, with a peak response at 10 nmol/L, and modulated GH-induced Janus kinase-2 (JAK2; 147796) phosphorylation in parallel with expression of surface GHRs. The abundance of GHR mRNA and protein, as assessed by RT-PCR and Western analysis, respectively, markedly increased with insulin treatment. Insulin suppressed surface translocation in a concentration-dependent manner, whereas internalization was unaffected. The authors concluded that insulin regulates hepatic GHR biosynthesis and surface translocation in a reciprocal manner, with surface receptor availability the net result of the divergent effects. The divergent actions of insulin appear to be mediated by the mitogen-activated protein kinase (MAPK; see 176948) and phosphatidylinositol 3-kinase (PI3K; see 601232) pathways, respectively.
Fisker et al. (2001) examined the gene expression of GHR and GHRtr in human adipose tissue and skeletal muscle and the influence of GH treatment on this expression. Furthermore, they studied the relationship of circulating GHBP and body composition to GHR and GHRtr gene expression. GHR expression in abdominal subcutaneous adipose tissue was not altered, whereas the expression of GHRtr increased significantly. In skeletal muscle, inverse changes were seen in the expression of mRNA levels for the 2 GH receptor forms: expression of GHR increased significantly, whereas mRNA levels for GHRtr decreased. As expected, body composition changed with reduction of body fat mass after 4 months of GH treatment. Levels of circulating GHBP decreased significantly. The authors concluded that GH treatment in GH-deficient adults changes the expression of mRNA for GHR and GHRtr in adipose tissue and skeletal muscle.
GH-binding protein (GHBP), which corresponds to the extracellular domain of the GH receptor, is complexed with about half of the GH in human plasma. It acts as a reservoir or buffer, damping the oscillations of plasma GH, prolonging GH half-life, and modulating GH bioactivity through competition with GHR for GH. In a review, Amit et al. (2000) discussed various aspects that might differentially affect GHR and GHBP, based on species and tissue divergence, regulation of cell-surface GHR turnover, GHR cleavage mechanism, or GHR mRNA splicing, and patients with growth hormone insufficiency with normal or high GHBP levels.
Binding of GH to GHR rapidly and transiently activates multiple signal transduction pathways that contribute to the growth-promoting and metabolic effects of GH. Stofega et al. (2000) examined the role of the SH2 (Src homology-2) domain-containing protein tyrosine phosphatase SHP2 (PTPN11; 176876) in GH signaling. They demonstrated that the SH2 domains of SHP2 bind directly to tyrosyl-phosphorylated GHR from GH-treated cells. A tyr595-to-phe mutation of rat GHR greatly diminished association of the SH2 domains of SHP2 with GHR, and a tyr487-to-phe mutation reduced association of the SH2 domains of SHP2 with GHR. Stofega et al. (2000) concluded that tyr595 is a major site of interaction of GHR with SHP2, and that GHR-bound SHP2 negatively regulates GHR/JAK2 and STAT5B (604260) signaling.
Using homo-fluorescence resonance energy transfer (homo-FRET) and other means, Brooks et al. (2014) tested whether GHR exists as a dimer in the inactive state. Then, to define receptor movements resulting from activation, Brooks et al. (2014) attached FRET reporters to the receptor below the cell membrane and correlated their movement with receptor activation, measured as increased cell proliferation. They also used FRET reporters to monitor the movement of JAK2 (147796), and matched this with molecular dynamics docking of the crystal structures of the kinase and its pseudokinase domains. Brooks et al. (2014) found that GHR exists predominantly as a dimer in vivo, held together by its transmembrane helices. These helices are parallel in the basal state, and binding of the hormone converts them into a left-hand crossover state that induces separation of helices at the lower transmembrane boundary. This movement is triggered by increased proximity of the juxtamembrane sequences, a consequence of locking together of the lower module of the extracellular domain on hormone binding. The key outcome is the separation of the Box1 sequences. Because these sequences are bound to the JAK2 FERM domains, this separation results in removal of the pseudokinase inhibitory domain of 1 JAK2, which is blocking the kinase domain of the other JAK2, and vice versa. This brings the 2 kinase domains into productive apposition, triggering JAK2 activation. Brooks et al. (2014) verified this mechanism by kinase-pseudokinase domain swap, by changes in JAK2 FRET signal on activation, by showing association of pseudokinase-kinase domain pairs, and by docking of the crystal structures.
Barton et al. (1989) used the cloned human GHR cDNA to map the GHR locus to human chromosome 5p13.1-p12 and to mouse chromosome 15 by Southern blot analysis and in situ hybridization.
Arden et al. (1989, 1990) confirmed the assignment of the GHR gene and showed, furthermore, that the prolactin receptor gene (176761) is located in the same region and presumably was derived from a common precursor.
Laron Syndrome
Mutations in the GHR gene have been demonstrated as the cause of Laron syndrome (262500), also known as the growth hormone insensitivity syndrome (GHIS) (Amselem et al. (1989, 1991)). The first 4 mutations discovered (600946.0001, 600946.0002, 600946.0003, 600946.0004) caused truncation of the GHR protein and deleted a large part of the GH-binding domain, consistent with the lack of binding activity of the plasma GH-binding protein observed in the patients; the whole transmembrane and intracellular domains were also deleted in the truncated protein (Amselem et al., 1991).
Berg et al. (1993) studied 7 unrelated affected individuals from the United States, South America, Europe, and Africa, and in each case identified a mutation likely to cause Laron syndrome, including 2 nonsense mutations (R43X, 600946.0003 and R217X, 600946.0009), 2 splice junction mutations (189-1G-T, 600946.0012 and 71+1G-A, 600946.0010), and 2 frameshift mutations (46delTT, 600946.0011 and 230delTA or AT, 600946.0013). Only 1 of the mutations, R43X, had previously been reported. Using haplotype analysis, Berg et al. (1993) determined that this mutation, which involved a CpG dinucleotide hotspot, likely arose as an independent event in their case, relative to the 2 prior reports of R43X. Aside from the recurrent R43X, the mutations they identified were unique to patients from particular geographic regions. All of the 10 GHR gene mutations identified in Laron syndrome to that time involved the extracellular domain of the receptor. Woods et al. (1996) reported the first homozygous point mutation within the intracellular domain of GHR in 2 cousins with Laron syndrome who were phenotypically distinguishable only by elevated levels of GH-binding protein in their serum; see 600946.0014.
The IGF1 (147440) generation test had been proposed to select patients with growth hormone insensitivity. To assess the reproducibility of the generation test, Jorge et al. (2002) studied a group of 12 prepubertal children with short stature and normal GH secretion in whom defects in the coding region of the GHR gene were ruled out. All patients underwent the test twice. Discordant responses between the first and second test were found in 5 and 6 patients for IGF1 and IGFBP3 (146732), respectively. The authors' findings showed that the IGF1 and IGFBP3 generation test was not reproducible in children that should have responded to GH stimulation. They suggested that, when IGF1 and IGFBP3 levels fail to respond in the generation test, another test should be performed to confirm GH insensitivity.
Wojcik et al. (1998) analyzed the GHR gene in 4 individuals with Laron syndrome. In each patient, a missense mutation was identified in the extracellular domain: D152H (600946.0021), I153T (600946.0022), Q154P (600946.0023), and V155G (600946.0024). In cells expressing the I153T and V155G mutants, binding of radioisotope-labeled human GH at the cell surface was very low, whereas binding to total membrane fractions was much less affected, suggesting impaired cell surface expression. Binding assays with cells expressing the Q154P mutant revealed severe defects both at the cell surface and in total particulate membrane fractions. Immunofluorescence experiments confirmed that cell surface expression of the 3 mutants was altered, and colocalization studies suggested that most of the mutant receptors are retained in the endoplasmic reticulum. The authors concluded that the I153T, Q154P, and V155G mutations mainly affect intracellular trafficking and binding affinity of the receptor, whereas the D152H mutation affects receptor expression, dimerization, and signaling.
Kaji et al. (1997) studied a girl with severe growth retardation, clinical features of Laron syndrome, and undetectable serum GHBP. They determined that she was a compound heterozygote for GHR mutations: substitution of glu224 with a stop codon (600946.0016) and a frameshift leading to premature termination at amino acid 330 (600946.0017). The authors concluded that neither mutant allele could produce a functional GHR.
Walker et al. (1998) reported a Vietnamese girl with Laron syndrome who had been treated with recombinant human IGF1 (147440) for 4 years, from age 11.28 years. Her height standard deviation (SD) score increased from -6.3 to -4.7 without acceleration of bone age. Isolated breast development progressed despite pubertal suppression with luteinizing hormone-releasing hormone analog, which was stopped after 3 years because of growth deceleration. Facial coarsening was documented with serial photographs. Sequencing and in vitro analysis identified homozygosity for a C-to-A transversion in exon 6 of the proband's GHR gene encoding a pro131-to-gln (P131Q; 600946.0019) substitution that was demonstrated to disrupt GH binding.
Gastier et al. (2000) identified a novel deletion removing part of exon 5 and 1.2 kb of the preceding intron as the cause of growth hormone insensitivity syndrome in a Cambodian family. The deletion occurred by recombination within 4 identical nucleotides. They identified a previously reported (Godowski et al., 1989) discontinuous deletion of GHR exons 3, 5, and 6 in 3 Oriental Jewish families. Other deletions were reported.
Growth hormone is used to increase height in short children who are not deficient in growth hormone, but its efficacy varies widely across individuals. Dos Santos et al. (2004) found that the d3GHR isoform (600946.0031) was associated with 1.7 to 2 times more growth acceleration induced by growth hormone than the full-length isoform (p less than 0.0001).
Audi et al. (2006) studied the frequencies of d3GHR and flGHR polymorphism genotypes in control and short small-for-gestational-age (SGA) populations. Their data showed significant differences in the frequency distribution of the d3GHR and flGHR genotypes between a normally distributed adult height population and short SGA children, with the biologically less active flGHR/flGHR genotype being almost twice as frequent in SGA patients. Audi et al. (2006) concluded that the d3/fl GHR polymorphism might contribute to the phenotypic expression of growth.
Partial Growth Hormone Sensitivity
Goddard et al. (1995) identified heterozygous mutations in the GHR gene (600946.0006, 600946.0007, 600946.0008) in 4 of 14 children with idiopathic short stature selected on the basis of normal growth hormone secretion and low serum concentrations of GH-binding protein. The patients were found to have partial growth hormone sensitivity (GHIP; 604271).
Ayling et al. (1997) reported a mother and daughter with idiopathic short stature, which they described as a 'new' category of autosomal dominant congenital GHIS caused by a dominant-negative mutation in the cytoplasmic domain of the GHR gene (600946.0015). Neither individual had any evidence of the phenotype usually associated with congenital GHIS (midfacial hypoplasia, blue sclera, limited elbow extension, sparse hair in childhood, or truncal adiposity). The abnormality was not detected in the maternal grandparents, indicating a de novo mutation in the proband's mother. A signal peptide and extracellular sequence of the GHR gene are encoded by exons 2 to 7 and the transmembrane domain by most of exon 8. The intracellular sequence is encoded by a small part of exon 8, together with exons 9 and 10. RT-PCR with primers located in exons 8 and 10 produced 2 bands of approximately 290 and 220 bp, suggesting that the mutation caused deletion of exon 9, which was confirmed by sequencing. The predicted consequence of the exon skipping was a frameshift resulting in a premature stop codon so that the cytoplasmic sequence of the mutant GHR would be reduced to only 7 amino acids. The GHR belongs to the cytokine superfamily of receptors that depend on JAK tyrosine kinases (see 147795) for activation of STATs (see 600555) and other signaling pathways. Association of JAK2 (147796) with the GHR requires a conserved proline-rich sequence encoded by exon 9, which is located in the cytoplasmic domain. Cotransfection of the mutant and wildtype GHR together with a reporter gene containing STAT5 (601511) binding sites showed that the mutant GHR was unable to activate STAT5. More importantly, the truncated receptor exerted a marked dominant-negative effect on GHR. Ayling et al. (1997) noted that ligand-induced dimerization of GHR is essential for signal transduction, and immunoprecipitation after cotransfecting cells with both forms of GHR showed that the wildtype and mutant forms heterodimerize. A specific cytoplasmic residue is necessary for internalization and degradation of the receptor, and this process is also dependent on ubiquitination of the cytoplasmic domain. Lacking these sequences, the mutant receptors would be expected to accumulate at the cell surface, reinforcing their dominant-negative effect. Overexpression of the mutant allele was also observed and appeared to contribute to the dominant-negative effect. Most previously identified mutations had been located in the extracellular hormone-binding domain of GHR, with consequent decrease in serum GH-binding protein (which is derived from this region of the receptor). The heterozygous mutations found by Goddard et al. (1995) as an apparent contributing factor to the problem in children with 'idiopathic' short stature and low GHBP were also located in the extracellular domain. An important implication of the study by Ayling et al. (1997) was that dominant GHR mutations should be sought in children who would not previously have been thought to have endocrinopathy, namely, those with familial short stature and normal GHBP.
Pantel et al. (2003) reported the first identification of a mutation in exon 3 of the GHR (W16X) in a patient with GH insensitivity who also carried another nonsense mutation in exon 4 (600946.0004). Intrafamilial correlation analyses of genotypes (presence of normal or mutant GHRfl and/or d3GHR alleles), GHR expression patterns, and phenotypes provided direct evidence against an alternative splicing of exon 3. In particular, this exon was retained into transcripts originating from the GHRfl-W16X allele in both the patient and his mother. The authors concluded from these observations, given the normal phenotype of the heterozygous parents, that a single copy of either GHRfl or d3GHR is sufficient for normal growth.
Possible Associations
Horan et al. (2006) observed an association between 4 core promoter haplotypes in the GH1 gene (139250) and increased risk for hypertension and stroke in a study of 111 hypertensive patients and 155 stroke patients. The association was more significant for females than males. Horan et al. (2006) also observed an association between d3GHR and hypertension in female stroke patients. The authors postulated a complex interaction between variants in the GH1 and GHR genes involving height.
Somatic Mutations
In 6 of 14 sparsely granulated human somatotroph adenomas (see 102200), Asa et al. (2007) identified somatic mutations in codon 49 (H49L or H49R) of the GHR gene within an extracellular cysteine-rich immunoglobulin-like loop encoded by exon 4. In vitro functional studies with mutant rabbit Ghr showed that the codon 49 mutations impaired receptor processing, activation, and binding of growth hormone. Mutant Ghr was retained within cytoplasmic granules in the endoplasmic reticulum, and there was relative resistance of mutant Ghr to activation of intracellular signaling by GH. Thus, mutant Ghr showed ineffective sensing of ambient GH and lacked negative feedback on GH production and growth, suggesting another pathogenetic mechanism for a subgroup of pituitary somatotroph adenomas. Asa et al. (2007) noted that the findings were significant for treatment, in that the disruption of GH autoregulation by a GHR mutation in sparsely granulated adenomas renders GHR antagonism a more appropriate therapeutic option than GH antagonism, since the former would be less likely to be associated with treatment-induced tumor activation.
Mercado et al. (2008) studied whether the GHR genotype, by modifying tissue sensitivity to GH, influences the clinical/biochemical expression of acromegaly (see 102200) and its outcome after treatment. They assessed prevalence of the 3 GHR genotypes fl/fl, d3/d3, and d3/fl, associations between the genotypes, and baseline as well as posttherapeutic characteristics. Multiple regression analysis revealed that the homo- or heterozygous lack of exon 3 was the strongest predictor of persistent biochemical activity. Mercado et al. (2008) concluded that the absence of exon 3 of the GHR may be associated with a more morbid acromegalic clinical and biochemical picture and a lower chance of achieving IGF1 normalization after therapy.
Leung et al. (1987) cloned the putative rabbit serum GHBP and GHR mRNAs, and deduced the corresponding amino acid sequences from the cDNA sequences. These receptors consist of 3 components: an extracellular region that presumably binds GH, a transmembrane region, and a cytoplasmic region. The N-terminal amino acid sequences of the rabbit GHR and the rabbit serum GHBP were found to be identical, suggesting that the GHBP was derived from the extracellular hormone-binding region of the GHR (Spencer et al., 1988).
Using GH-deficient Socs2 (605117) -/- mice, Greenhalgh et al. (2005) demonstrated that the Socs2 -/- phenotype is dependent upon the presence of endogenous GH. Treatment with exogenous GH induced excessive growth in terms of overall body weight, body and bone lengths, and the weight of internal organs and tissues. Microarray analysis on liver RNA extracts after exogenous GH administration revealed a heightened response to GH. The conserved C-terminal SOCS-box motif was essential for all inhibitory function. SOCS2 was found to bind 2 phosphorylated tyrosines (at codons 487 and 595) on the GH receptor, and mutation analysis of these amino acids showed that both were essential for SOCS2 function. Greenhalgh et al. (2005) concluded that SOCS2 is a negative regulator of GH signaling.
Rubin et al. (2010) described the use of massively parallel sequencing to identify selective sweeps of favorable alleles and candidate mutations that have had a prominent role in the domestication of chickens and their subsequent specialization into broiler (meat-producing) and layer (egg-producing) chickens. Rubin et al. (2010) generated 44.5-fold coverage of the chicken genome using pools of genomic DNA representing 8 different populations of domestic chickens as well as red jungle fowl (Gallus gallus), the major wild ancestor. Rubin et al. (2010) reported more than 7,000,000 SNPs, almost 1,300 deletions, and a number of putative selective sweeps. One of the most striking selective sweeps found in all domestic chickens occurred at the locus for thyroid-stimulating hormone receptor (TSHR; 603372), which has a pivotal role in metabolic regulation and photoperiod control of reproduction in vertebrates. Several of the selective sweeps detected in broilers overlapped genes associated with growth, including growth hormone receptor (600946), appetite, and metabolic regulation. Rubin et al. (2010) found little evidence that selection for loss-of-function mutations had a prominent role in chicken domestication, but they detected 2 deletions in coding sequences, including one in SH3RF2 (613377), that the authors considered functionally important.
Characterization of the GHR gene from 9 patients with Laron syndrome (262500) showed that 2 had a deletion of a large portion of the extracellular, hormone-binding domain (Godowski et al., 1989). Interestingly, this deletion included nonconsecutive exons, suggesting that an unusual rearrangement may have occurred.
By an analysis of the GHR mRNA transcripts in lymphocytes from a Mediterranean patient with Laron syndrome (262500), Amselem et al. (1989) demonstrated a thymidine-to-cytosine substitution that generated a serine in place of a phenylalanine at position 96 in the extracellular coding domain of the protein. The mutation was not found in 7 unrelated subjects with Laron syndrome who belonged to different population groups; in these families, the GHR markers showed a different haplotype background for the mutation.
Duquesnoy et al. (1991) investigated the effect of the phe96-to-ser mutation on GH-binding activity by expressing the total human GHR cDNA and the mutant form in eukaryotic cells. Cells transfected with the mutant cDNA lacked binding activity. Specific GH-binding activity was found, however, in the lysosomal fraction, and immunofluorescence studies located mutant proteins in the cytosol. The findings suggested that mutant GHRs fail to follow the correct intracellular transport pathway and underscored the potential importance of the phenylalanine residue, which is conserved among the GH, prolactin, and erythropoietin (133171) receptors that belong to the same cytokine receptor superfamily. Edery et al. (1993) introduced the F96S mutation by site-directed mutagenesis into cDNAs encoding the full-length rabbit GHR and the extracellular domain or binding protein of the human and rabbit GHR. All constructs were transiently expressed in COS-7 cells, and expression of the receptors was assessed by Western blot and immunofluorescence studies. Wildtype and mutant full-length GHR had the same cell surface and intracellular distribution and were expressed with comparable intensities. In contrast, all mutant forms completely lost their ability to bind ligand. Thus, this mutation does not modify the synthesis or the intracellular pathway of receptor proteins, but rather abolishes ability of the receptor or binding protein to bind GH and is thereby responsible for the extreme GH resistance in these patients.
In 2 Mediterranean patients with Laron syndrome (262500), born of consanguineous marriages, Amselem et al. (1990, 1991) found a C-to-T substitution at position 181 in exon 4 of the GHR gene, which resulted in an arg43-to-ter substitution. The nature of this mutation (CG-to-TG) was consistent with the accidental deamination of a 5-methylcytosine in a CpG doublet. The mutation was associated with 2 different GHR DNA haplotypes, suggesting recurring mutations. Berg et al. (1993) found the same mutation, but from haplotype analysis concluded that it had arisen independently.
In a patient of northern European ethnicity with Laron syndrome (262500), Amselem et al. (1990, 1991) found a point mutation in exon 4 of the GHR gene that converted cysteine (TGC) to a premature termination signal (TGA) at codon 38.
In 37 patients with Laron syndrome (262500) living in Ecuador (Rosenbloom et al., 1990), Berg et al. (1992) identified a mutation in the GHR gene by use of denaturing gradient gel electrophoresis. In obligate heterozygotes, only exon 6 revealed homo- and heteroduplexes, and sequencing revealed a substitution of guanine for adenine at the third position of codon 180 (for glutamic acid) that did not change the amino acid encoded. Sequencing of the exon 6/exon 7 splice junction from PCR-amplified cellular RNA of an affected person showed that the substitution activated a cryptic splice site 24 nucleotides upstream from the normal exon 6/intron 6 boundary. The codon 180 nucleotide substitution (E180) would be predicted to result in an abnormally spliced GHR transcript that would lead to the synthesis of a receptor protein with an 8-amino acid deletion from the extracellular domain.
Superior school performance was reported for 52 Ecuadorian probands with severe deficiency of insulin-like growth factor I due to GHR deficiency (GHRD) resulting from homozygosity for the GHR E180 splice mutation. Kranzler et al. (1998) evaluated the intellectual ability of patients with GHRD, using a battery of intelligence tests that had been validated in cross-cultural research and designed to minimize the effects of physical size, motor coordination, and cultural background. Because all patients had the same GHR mutation, for which the carrier state could be determined, this study also investigated whether heterozygosity for mutation of the GHR among unaffected relatives is associated with intelligence. The intellectual ability of the patients with GHRD was not significantly different from that of their relatives (P greater than 0.05) on the psychometric tests of intelligence and was comparable to that of the community controls on the chronometric tests. Homozygosity or heterozygosity for the mutation in the GHR gene common to Ecuadorian patients was unrelated to intelligence (P greater than 0.05).
Rosenbloom et al. (1998) studied a population in Ecuador in which 70 individuals with GHR deficiency were homozygous for the E180 splice mutation. They found that 58 heterozygous relatives of probands were not significantly shorter than 37 homozygous normal relatives (standard deviation (SD) score for height - 1.85 +/- 1.04 vs -1.55 +/- 0.96, P greater than 0.10). When only those families with both homozygous normals and carriers were compared, the 33 heterozygous and 29 normal relatives also did not differ significantly in height SD scores (-1.98 +/- 1.07 vs -1.77 +/- 0.91, P greater than 0.3). The authors concluded that heterozygosity for the E180 splice mutation of the GHR has no meaningful effect on stature.
Disorders of GH secretion are known to impair the physiologic lipostat and to affect the secretion of leptin (164160), a sensitive marker of regional fat accumulation and total body composition. To examine the impact of different forms of growth disorders on leptin production, Marzullo et al. (2002) measured leptin levels in 22 growth hormone insensitivity (GHI) patients homozygous for the GHR E180 splice mutation and compared results with those obtained in 20 subjects heterozygous for the mutation, 17 idiopathic growth hormone deficiency (GHD) patients, and 44 normal subjects. IGFI (147440) and IGFBP3 (146732) levels were significantly lower (P less than 0.0001) in homozygous GHI and GHD patients compared with either controls or GHI heterozygotes. Circulating leptin levels were significantly higher in homozygous GHI patients than in normal controls as well as when compared with heterozygous GHI subjects and GHD patients (P less than 0.01). Similar results were obtained when leptin was normalized for body mass index. The authors concluded that leptin is increased in patients affected with long-standing homozygous GHI, probably reflecting abnormalities of body composition and metabolism typical of this condition.
In a child with partial growth hormone sensitivity and short stature (GHIP; 604271), who had normal growth hormone secretion and low serum concentrations of GH-binding protein, Goddard et al. (1995) found compound heterozygosity for a G-to-A transition at position 184 in exon 4 of the GHR gene, resulting in a glu44-to-lys amino acid substitution, and a C-to-T transition at position 535 in exon 6, resulting in an arg161-to-cys amino acid substitution (600946.0007). Goddard et al. (1995) noted that the child was more severely affected than his heterozygous parents.
For discussion of the C-to-T transition at position 535 in exon 6 of the GHR gene, resulting in an arg161-to-cys (R161C) substitution, that was found in compound heterozygous state in a child with partial growth hormone sensitivity and short stature (GHIP; 604271), who had normal growth hormone secretion and low serum concentrations of GH-binding protein, by Goddard et al. (1995), see 600946.0006.
In a patient with idiopathic partial growth hormone sensitivity and short stature (GHIP; 604271), Goddard et al. (1995) found a mutation at nucleotide position 726 of the GHR gene that introduced an aspartic acid in place of glutamic acid at position 224. Neither analysis of single-strand conformation polymorphisms nor direct sequencing of the region of the gene that coded for the extracellular domain identified a second mutation in this patient.
Berg et al. (1993) found a homozygous R217X mutation in the GHR gene in an African American patient with Laron syndrome (262500).
In a Spanish patient with Laron syndrome (262500) and nonconsanguineous parents, Berg et al. (1993) found compound heterozygosity for a donor splice site mutation and for a frameshift mutation resulting from deletion of 2 bp (TT) at codon 46 (600946.0011). The authors designated the splice site mutation as 71+1 G to A.
In 2 unrelated Spanish patients with Laron syndrome (262500), Berg et al. (1993) found homozygosity for a deletion of TT at codon 46 in one and compound heterozygosity for this mutation in the second. The 2-bp deletion resulted in a nonsense mutation 5 codons downstream from codon 46. The parents were consanguineous in the first family, but were not consanguineous in the second.
In a consanguineous Brazilian case of Laron syndrome (262500), Berg et al. (1993) found a G-to-T transversion at position -1 in the splice acceptor site of intron 6. The authors designated the mutation as 189-1G-T. The patient was homozygous for the mutation.
In a South African patient with Laron syndrome (262500) and nonconsanguineous parents, Berg et al. (1993) found homozygosity for deletion of either TA or AT at codon 230 in exon 7 of the GHR gene.
Woods et al. (1996) reported the first homozygous point mutation within the intracellular domain of GHR in 2 Laron syndrome (262500) cousins distinguishable from classic Laron syndrome patients only by the presence of elevated GH-binding protein in their serum. Woods et al. (1996) detected a G-to-C transversion of the last nucleotide of exon 8 (nucleotide 91 of exon 8; the authors referred to the position of the mutation as 'the -1 position of the 5-prime splice donor site of exon 8'). The mutation was predicted to result in replacement of arginine by threonine at amino acid 274 (R274T); direct sequencing of RT-PCR products from 1 patient demonstrated that exon 8 was skipped in GHR mRNA, resulting in exon 7 splicing into exon 9. The skipping of exon 8 (encoding the transmembrane domain) in the GHR mRNA also resulted in exon 9 (encoding the beginning of the intracellular domain) being translated out of frame with a stop codon 5 amino acids downstream. Woods et al. (1996) predicted that this mutant protein would not be anchored in the cell membrane and would be measurable in the circulation as GHBP, thus explaining the phenotype of severe GH resistance combined with elevated circulating GHBP.
In a mother and daughter with partial growth hormone insensitivity and short stature (GHIP; 604271), Ayling et al. (1997) identified a G-to-C transversion at the -1 position in the 3-prime splice acceptor site preceding exon 9 of the GHR gene. They demonstrated that this mutation had a dominant-negative effect. The mutation caused a truncation of the cytoplasmic portion of the protein and was associated with normal serum GH-binding protein (GHBP). Virtually all mutations previously identified were located in the extracellular hormone-binding domain of the GH receptor. Their findings in this family indicated that dominant GHR mutations should be sought in the group of children who had not previously been thought to have an endocrinopathy, namely, those with familial short stature and normal GHBP.
Kaji et al. (1997) reported a girl with severe growth retardation and clinical features of Laron syndrome (262500) whose serum insulin-like growth factor-1 (IGF1; 147440) was unresponsive to exogenous GH administration. The serum GHBP level was undetectable in the girl, but it was normal in her parents and brother who were normal in their height. Analysis revealed that she was a compound heterozygote for GHR mutations. The GHR allele from her mother contained a G-to-T transversion in exon 7 that results in a glu224-to-ter substitution; the allele from her father, also identified in her brother, contained a frameshift that results in premature termination at residue 330 (600946.0017). The authors concluded that neither of the mutant alleles could encode a functional GHR, consistent with the patient's severe growth retardation and undetectable serum GHBP.
By PCR and direct sequencing, Kaji et al. (1997) identified compound heterozygous GHR mutations in a girl with severe growth retardation, Laron syndrome (262500), and undetectable serum GHBP. The allele inherited from her mother contained a glu224-to-ter substitution (600946.0016). The allele from her father contained a C deletion at position 981 in exon 10 that causes a frameshift, resulting in 20 novel amino acids (310 to 329), premature termination at codon 330, and deletion of the C-terminal portion of the intracellular domain of GHR. RT-PCR of her father's lymphocytes revealed that only the wildtype GHR mRNA was expressed.
Iida et al. (1998) found a heterozygous point mutation of the donor splice site in intron 9 of the GHR gene in 2 Japanese sibs with Laron syndrome (262500), whose serum GHBP levels were high, and their mother. Analysis of mRNA from the peripheral leukocytes revealed complete skipping of exon 9 from 1 GHR allele, but not the other, and appearance of a premature stop codon in exon 10. The translated GHR protein was truncated with deletion of 98% of its intracellular domain, including boxes 1 and 2, which are critical for GH signal transduction and GHR internalization, respectively. It was shown that the truncated GHR lacking the intracellular domain was physiologically present in a minute amount, served as a negative regulator for GH signaling, and possessed increased capacity to generate GHBP. The authors concluded that this mutation causes production of a truncated GHR that has a dominant-negative effect on GH signaling, which probably causes the short stature and high serum GHBP levels seen in these patients.
Iida et al. (1999) characterized the effect of the IVS9 +1 G-to-A mutation in COS-7 and CHO cells in vitro. Scatchard analysis showed that the mutant GHR possessed approximately 1.5 times higher affinity to GH and twice the number of binding sites compared to wildtype full-length GHR. The GHBP level in culture medium of cells expressing the mutant receptor was approximately 3 times higher than that in the normal GHR-expressing cells. The mutant GHR exerted a dominant-negative effect when cotransfected with normal GHR. The authors concluded that these data explained the clinical characteristics of their patients showing high serum GHBP levels and development of short stature despite heterozygosity for the IVS9 +1 G-to-A mutation.
In a Vietnamese girl with Laron syndrome (262500), Walker et al. (1998) identified homozygosity for a C-to-A transversion in exon 6 of the GHR gene, encoding a pro131-to-gln (P131Q) substitution. Both the mutant and normal GHR were transiently expressed in COS-1 cells; cells transfected with the mutant did not bind GH. From examination of the crystal structure of the GHR, the authors suggested that the P131Q mutation disrupts the interdomain link between the extracellular domains of the GHR, causing a conformational change that results in disruption of the GH binding site.
Sanchez et al. (1998) analyzed the GHR gene in 17 subjects with partial growth hormone insensitivity and short stature (GHIP; 604271). A novel heterozygous mutation (c.484G-A) in exon 6 resulting in a val144-to-ile substitution in the extracellular domain was found in 1 subject (height, -1.8 SD). The mutation was also found in his mother and 1 brother, both of whom had significant short stature (height, -2.5 SD and -2.3 SD, respectively). Affected family members also had a polymorphism in exon 6 of the GHR gene (c.168A-G); the authors noted that this polymorphism had been reported in other subjects with short stature and heterozygous mutations of the GHR gene. None of the affected members of this family had any features of growth hormone insensitivity syndrome (Laron syndrome).
In a patient with Laron syndrome (262500), Wojcik et al. (1998) detected a homozygous G-to-C transversion in the GHR gene resulting in substitution of histidine for asparagine at codon 152 (D152H).
In a patient with Laron syndrome (262500), Wojcik et al. (1998) detected a T-to-C transition in the GHR gene resulting in a substitution of threonine for isoleucine at codon 153 (I153T). The mutation was found in heterozygous state.
In a patient with Laron syndrome (262500), Wojcik et al. (1998) detected a homozygous A-to-C transversion in the GHR gene which resulted in a gln154-to-pro substitution (Q154P).
In a patient with Laron syndrome (262500), Wojcik et al. (1998) detected a homozygous T-to-G transversion in the GHR gene resulting in a val155-to-gly (V155G) amino acid substitution.
Metherell et al. (2001) studied a highly consanguineous Pakistani kindred in which 4 males (2 pairs of sibs) had atypical growth hormone insensitivity (262500). All 4 patients had marked short stature and normal facial appearance. They had low levels of IGF1 and detectable levels of growth hormone-binding protein. By homozygosity mapping of several polymorphic markers surrounding the GHR gene, Metherell et al. (2001) found in all 4 patients a homozygous region that was absent in their unaffected sibs. They identified a novel point mutation in GHR that led to activation of an intronic pseudoexon resulting in inclusion of an additional 108 nucleotides between exons 6 and 7 in most GHR transcripts. The mutation was an A-to-G change at position -1 of the acceptor splice site at the 5-prime end of the pseudoexon. Under in vitro splicing conditions, the mutation resulted in inclusion of the mutant pseudoexon, whereas the wildtype pseudoexon was skipped. The presence of the pseudoexon resulted in inclusion of an additional 36 amino acids in a region of the receptor known to be involved in homodimerization, which is essential for signal transduction.
David et al. (2007) studied the clinical and genetic characteristics of additional GHI patients with this mutation. One patient was from the extended family previously reported by Metherell et al. (2001). She had normal facial features, and her IGF1 levels were in the low-normal range for age. The 6 unrelated patients, 4 of whom had typical Laron syndrome facial features, had heights ranging from -3.3 to -6.0 SD and IGF1 levels that varied from normal to undetectable. They hypothesized that the marked difference in biochemical and clinical phenotypes may be caused by variations in the splicing efficiency of the pseudoexon. Since activation of the pseudoexon in the GHR gene can lead to a variety of GHI phenotypes, David et al. (2007) advocated screening for the presence of this mutation in all GHI patients without mutations in the coding exons.
In a 53-year-old woman and her 57-year-old brother with growth hormone insensitivity syndrome (262500), Milward et al. (2004) identified a homozygous 22-bp deletion in exon 10 of the GHR gene. The mutation was predicted to result in frameshift introducing novel codons from positions 424 through 449 followed by premature termination at codon 450. The predicted protein would lack a large portion of the intracellular domain. In the truncated protein, the membrane proximal region containing Box1 and Box2, critical for activation of JAK2 (147796) and STAT3 (102582), would be intact, but the protein would lack the C-terminal tyrosine residues essential for STAT5 (601511) activation. No STAT5 activity was detected in cells expressing the truncated protein, consistent with its lack of a STAT5 binding site. The authors concluded that the loss of signaling through the STAT5 pathway results in growth hormone insensitivity syndrome.
In a patient with typical Laron syndrome (262500), the child of unrelated and phenotypically normal German parents, Pantel et al. (2003) identified compound heterozygosity for the GHR cys38-to-ter mutation (600946.0004) and a novel G-to-A transition in exon 3 that replaced tryptophan by a premature termination signal at codon 16 (W16X). The father carried the C38X mutation in heterozygosity, while the mother appeared to be homozygous for the W16X mutation. A multiplex PCR experiment designed to look for the presence of exon 3 at the genomic level revealed that the patient and his father bore the homozygous full-length isoform (GHRfl/GHRfl), whereas the patient's mother carried deletion of exon 3 (600946.0031) in the heterozygous state (GHRfl/GHRd3). Pantel et al. (2003) concluded that a single copy of either GHRfl or GHRd3 is sufficient for normal growth.
Through molecular study of a 1,135-member American Caucasian kindred with familial hypercholesterolemia (143890), Takada et al. (2003) found that a SNP in the GHR gene, resulting in a leu526-to-ile (L526I) substitution, influenced plasma levels of high density lipoprotein (HDL) cholesterol in affected family members with a mutation in the LDLR gene causing hypercholesterolemia (IVS14+1G-A; 606945.0063). The lowest levels of plasma HDL were observed among leu/leu homozygotes, highest levels among ile/ile homozygotes, and intermediate levels among leu/ile heterozygotes. No such effect was observed among noncarriers of the LDLR mutation. The L526I substitution occurs in the cytoplasmic domain of the protein, and Takada et al. (2003) speculated that it may result in changes in downstream signal transduction.
In a 17-year-old female with characteristic features of Laron syndrome (262500), Tiulpakov et al. (2005) found compound heterozygosity for mutations in the GHR gene. One mutation was a C-to-A transversion at position 346 in exon 5 resulting in a premature termination at cysteine-83 (C83X). The other mutation was a 1-bp deletion (600946.0030).
One of the mutations in the GHR gene in the patient with Laron syndrome (262500) described by Tiulpakov et al. (2005) was a deletion of a guanine nucleotide at position 1776 in exon 10. The other was a premature termination mutation (600946.0029). The 1776del mutation was predicted to result in GHR truncation to 581 amino acids with a nonsense sequence of residues 560 to 581. After incubation with recombinant human GH, the 1776del mutant GHR showed approximately 50% lower STAT5 (601511)-mediated transcriptional activation as well as reduced STAT5 tyr694 phosphorylation compared with wildtype GHR. In contrast, the 1776del mutant vector produced a similar effect on STAT3 (102582)-mediated transcriptional activation as wildtype. The authors concluded that the GHR 1776del mutation in a classical growth hormone insensitivity patient illustrates an important mechanism of impaired GHR-STAT5 but intact GHR-STAT3 signaling. This effect might result from interference of C-terminal nonsense sequence in mutated GHR with STAT5 docking to upstream tyrosine residues.
In humans, GHR transcripts are present in 2 isoforms that differ by the retention or exclusion of exon 3. Pantel et al. (2000) demonstrated that the GHR isoform that lacks exon 3 (d3GHR) is transcribed from a gene that carries a 2.7-kb deletion spanning exon 3 and its flanking sequences. This deletion results in the loss of amino acid residues 7 through 28 and an ala6-to-asp (A6D) substitution in the terminal part of the extracellular receptor domain. The d3GHR allele results in increased sensitivity to therapeutically administered GH (see 604271).
Growth hormone is used to increase height in short children who are not deficient in growth hormone, but its efficacy varies widely across individuals. Dos Santos et al. (2004) found that the isoform of the GHR gene that lacks exon 3 (d3GHR) was associated with 1.7 to 2 times more growth acceleration induced by growth hormone than the full-length isoform (p less than 0.0001). In transfection experiments, the transduction of growth hormone signaling through d3GHR homo- or heterodimers was approximately 30% higher than through full-length GHR homodimers (p less than 0.0001). Dos Santos et al. (2004) stated that one-half of Europeans are heterozygous or homozygous with respect to the allele encoding the d3GHR isoform, which is dominant over the full-length isoform. Thus, the polymorphism in exon 3 of GHR is important in growth hormone pharmacogenetics. Transfective dose-response studies in all categories of children treated with growth hormone would determine the optimal growth hormone dosage for their GHR genotype. This may contribute to a switch from fixed dosage therapy to a more personalized adjustment of dose.
In short non-GH-deficient short-for-gestational-age (SGA) children, Carrascosa et al. (2006) found that both spontaneous growth rate and responsiveness to 66 microg/kg per day of GH therapy were similar for each d3/fl-GHR genotype carried. Carrascosa et al. (2008) hypothesized that higher doses of GH would mask the lower dose differences seen in the response of those with d3/fl-GHR genotypes. They evaluated, in short SGA patients, 2-year growth response to GH therapy (32.1 +/- 3.8 microg/kg per day) according to d3/fl-GHR genotype. They found that in short SGA children, 2-year growth response to GH therapy at this dosage was similar for each d3/fl-GHR genotype carried, as occurred in their previous study (Carrascosa et al., 2006). In a study of 219 short SGA children, of which 60 had entered puberty, Audi et al. (2008) found that d3/fl-GHR genotypes did not seem to influence prepubertal or pubertal insulin sensitivity indexes or their changes over 2 years of GH therapy.
Binder et al. (2006) tested the association of the d3GHR polymorphism in 2 distinct groups of rhGH-treated patients, short girls with Turner syndrome and short children born SGA. No significant difference in height, spontaneous height velocity, IGF1, and IGFBP3 levels was found at the start of the rhGH therapy in the 3 GHR genotype groups studied. At the first year of treatment, girls with Turner syndrome carrying 1 or 2 d3GHR alleles showed a significantly higher increment in height velocity (P = 0.019) and exceeded their growth prediction significantly (P = 0.007), whereas their increments of IGF1 and IGFBP3, weight, and height were not significantly different. Carriers of d3GHR in the group of short children born SGA grew significantly faster than predicted (P = 0.023). However, in comparison to the carriers of full-length GHR, gain of height velocity was not significantly higher (P = 0.067). The mean gain of height associated with d3GHR accounted for approximately 0.75 cm in SGA and 1.5 cm in Turner syndrome during the first year of rhGH therapy. Their data supported the theory that there is increased responsiveness to high-dose rhGH in association with the d3GHR genotype. The magnitude of this effect may depend on the primary origin of the short stature.
Jorge et al. (2006) performed a genotype and retrospective analysis on data of 75 patients with severe GHD. They found that patients who had at least 1 d3GHR allele had a small but statistically significant higher first-year growth response and taller final height after hGH treatment than patients who were homozygous for the GHRfl allele, treated under the same conditions.
In a study of 368 healthy adult women, Kenth et al. (2007) found no correlation between the GHR exon 3 genotype and final adult height and bone mineral density.
In a study of 115 healthy adolescents who were divided into those born SGA and appropriate for gestational age with or without intrauterine growth restriction, Jensen et al. (2007) found that the d3GHR allele was associated with increased spontaneous postnatal growth velocity, but with decreased fetal growth velocity in the SGA group.
Schreiner et al. (2007) studied association of the GHRd3 isoform with postnatal catch-up growth in very low birth weight preterm infants. Children homozygous or heterozygous for the GHRd3 allele showed a significantly higher rate of postnatal catch-up, compared with those homozygous for GHRfl allele. They concluded that their results define the GHR exon 3 genotype as a predictor for the postnatal growth pattern of very low birth weight preterm infants. Those who carry at least one GHRd3 allele are more likely to catch up.
In 181 subjects with severe isolated GH deficiency treated with recombinant human GH, Raz et al. (2008) studied the impact of exon 3 GHR genotype in terms of the initial height velocity (HV) resulting from treatment and upon adult height. After the first 2 years on recombinant human GH treatment, HV SD score (SDS) as well as height gain were greater in subjects with the GHR d3/d3 genotype when compared with the subjects presenting with the GHR fl/fl genotype. A GHR d3 allele dose-dependent effect was found for both HV SDS and height gain. However, there was no significant difference in final adult height and height SDS according to the exon 3 genotypes.
In a study of 99 adult GH-deficient patients receiving recombinant human GH (rhGH) replacement therapy, Van der Klaauw et al. (2008) found that the d3GHR genotype was associated with differences in efficacy of short-term (1 year), but not long-term (5 years), rhGH replacement with respect to IGF1 and lipid metabolism.
In 2 sisters with Laron syndrome (262500) from a nonconsanguineous Austrian family, Fang et al. (2007) identified compound heterozygosity for 2 mutations in the GHR gene: a G-to-C transversion in exon 5, resulting in a cys94-to-ser (C94S) substitution, inherited from the father; and a T-to-G transversion in exon 6, resulting in a his150-to-gln (H150Q; 600946.0033) substitution, inherited from the mother. In vitro reconstitution experiments showed that whereas each of the mutants could be stably expressed, C94S lost its affinity for GH and could neither activate STAT5B (604260) nor drive STAT5B-dependent gene transcription in response to GH (1-100 ng/ml). Fang et al. (2007) concluded that each of the compound heterozygous mutations contributed additively to the GHI. Both of the mutations are located in the extracellular domain of the GHR. Functional studies suggested that the C94S heterozygous state may cause partial GHI, although the impact on growth appeared to be modest.
For discussion of the T-to-G transversion in the GHR gene, resulting in a his150-to-gln (H150Q) substitution, that was found in compound heterozygous state in sisters with Laron syndrome (262500) by Fang et al. (2007), see 600946.0032.
Amit, T., Bergman, T., Dastot, F., Youdim, M. B. H., Amselem, S., Hochberg, Z. A membrane-fixed, truncated isoform of the human growth hormone receptor. J. Clin. Endocr. Metab. 82: 3813-3817, 1997. [PubMed: 9360546] [Full Text: https://doi.org/10.1210/jcem.82.11.4358]
Amit, T., Youdim, M. B. H., Hochberg, Z. Does serum growth hormone (GH) binding protein reflect human GH receptor function? J. Clin. Endocr. Metab. 85: 927-932, 2000. [PubMed: 10720017] [Full Text: https://doi.org/10.1210/jcem.85.3.6461]
Amselem, S., Duquesnoy, P., Attree, O., Novelli, G., Bousnina, S., Postel-Vinay, M.-C., Goossens, M. Laron dwarfism and mutations of the growth hormone-receptor gene. New Eng. J. Med. 321: 989-995, 1989. [PubMed: 2779634] [Full Text: https://doi.org/10.1056/NEJM198910123211501]
Amselem, S., Sobrier, M. L., Duquesnoy, P., Dallapiccola, B., Gourmelen, M., Rappaport, R., Goossens, M. Recurrent nonsense mutations in the human growth hormone-receptor gene. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A107, 1990.
Amselem, S., Sobrier, M.-L., Duquesnoy, P., Rappaport, R., Postel-Vinay, M.-C., Gourmelen, M., Dallapiccola, B., Goossens, M. Recurrent nonsense mutations in the growth hormone receptor from patients with Laron dwarfism. J. Clin. Invest. 87: 1098-1102, 1991. [PubMed: 1999489] [Full Text: https://doi.org/10.1172/JCI115071]
Arden, K. C., Boutin, J.-M., Djiane, J., Kelly, P. A., Cavenee, W. K. The receptors for prolactin and growth hormone are localized in the same region of human chromosome 5. Cytogenet. Cell Genet. 53: 161-165, 1990. [PubMed: 2369845] [Full Text: https://doi.org/10.1159/000132919]
Arden, K. C., Cavenee, W. K., Boutin, J.-M., Kelly, P. A. The genes encoding the receptors for prolactin and growth hormone map to human chromosome 5. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A129 only, 1989.
Asa, S. L., DiGiovanni, R., Jiang, J., Ward, M. L., Loesch, K., Yamada, S., Sano, T., Yoshimoto, K., Frank, S. J., Ezzat, S. A growth hormone receptor mutation impairs growth hormone autofeedback signaling in pituitary tumors. Cancer Res. 67: 7505-7511, 2007. [PubMed: 17671221] [Full Text: https://doi.org/10.1158/0008-5472.CAN-07-0219]
Audi, L., Carrascosa, A., Esteban, C., Fernandez-Cancio, M., Andaluz, P., Yeste, D., Espadero, R., Granada, M. L., Wollmann, H., Fryklund, L., Spanish SGA Study Group. The exon 3-deleted/full-length growth hormone receptor polymorphism does not influence the effect of puberty or growth hormone therapy on glucose homeostasis in short non-growth hormone-deficient small-for-gestational-age children: results from a two-year controlled prospective study. J. Clin. Endocr. Metab. 93: 2709-2715, 2008. [PubMed: 18445665] [Full Text: https://doi.org/10.1210/jc.2008-0150]
Audi, L., Esteban, C., Carrascosa, A., Espadero, R., Perez-Arroyo, A., Arjona, R., Clemente, M., Wollmann, H., Fryklund, L., Parodi, L. A., The Spanish SGA Study Group. Exon 3-deleted/full-length growth hormone receptor polymorphism genotype frequencies in Spanish short small-for-gestational-age (SGA) children and adolescents (n = 247) and in an adult control population (n = 289) show increased fl/fl in short SGA. J. Clin. Endocr. Metab. 91: 5038-5043, 2006. [PubMed: 17003087] [Full Text: https://doi.org/10.1210/jc.2006-0828]
Ayling, R. M., Ross, R., Towner, P., Von Laue, S., Finidori, J., Moutoussamy, S., Buchanan, C. R., Clayton, P. E., Norman, M. R. A dominant-negative mutation of the growth hormone receptor causes familial short stature. (Letter) Nature Genet. 16: 13-14, 1997. [PubMed: 9140387] [Full Text: https://doi.org/10.1038/ng0597-13]
Ballesteros, M., Leung, K.-C., Ross, R. J. M., Iismaa, T. P., Ho, K. K. Y. Distribution and abundance of messenger ribonucleic acid for growth hormone receptor isoforms in human tissues. J. Clin. Endocr. Metab. 85: 2865-2871, 2000. [PubMed: 10946895] [Full Text: https://doi.org/10.1210/jcem.85.8.6711]
Barton, D. E., Foellmer, B. E., Wood, W. I., Francke, U. Chromosome mapping of the growth hormone receptor gene in man and mouse. Cytogenet. Cell Genet. 50: 137-141, 1989. [PubMed: 2776481] [Full Text: https://doi.org/10.1159/000132743]
Berg, M. A., Argente, J., Chernausek, S., Gracia, R., Guevara-Aguirre, J., Hopp, M., Perez-Jurado, L., Rosenbloom, A., Toledo, S. P. A., Francke, U. Diverse growth hormone receptor gene mutations in Laron syndrome. Am. J. Hum. Genet. 52: 998-1005, 1993. [PubMed: 8488849]
Berg, M. A., Guevara-Aguirre, J., Rosenbloom, A. L., Rosenfeld, R. G., Francke, U. Mutation creating a new splice site in the growth hormone receptor genes of 37 Ecuadorean patients with Laron syndrome. Hum. Mutat. 1: 24-34, 1992. [PubMed: 1284474] [Full Text: https://doi.org/10.1002/humu.1380010105]
Binder, G., Baur, F., Schweizer, R., Ranke, M. B. The d3-growth hormone (GH) receptor polymorphism is associated with increased responsiveness to GH in Turner syndrome and short small-for-gestational-age children. J. Clin. Endocr. Metab. 91: 659-664, 2006. [PubMed: 16291706] [Full Text: https://doi.org/10.1210/jc.2005-1581]
Brooks, A. J., Dai, W., O'Mara, M. L., Abankwa, D., Chhabra, Y., Pelekanos, R. A., Gardon, O., Tunny, K. A., Blucher, K. M., Morton, C. J., Parker, M. W., Sierecki, E., Gambin, Y., Gomez, G. A., Alexandrov, K., Wilson, I. A., Doxastakis, M., Mark, A. E., Waters, M. J. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science 344: 1249783, 2014. Note: Electronic Article. [PubMed: 24833397] [Full Text: https://doi.org/10.1126/science.1249783]
Carrascosa, A., Audi, L., Esteban, C., Fernandez-Cancio, M., Andaluz, P., Gussinye, M., Clemente, M., Yeste, D., Albisu, M. A. Growth hormone (GH) dose, but not exon 3-deleted/full-length GH receptor polymorphism genotypes, influences growth response to two-year GH therapy in short small-for-gestational-age children. J. Clin. Endocr. Metab. 93: 147-153, 2008. [PubMed: 17925340] [Full Text: https://doi.org/10.1210/jc.2007-1182]
Carrascosa, A., Esteban, C., Espadero, R., Fernandez-Cancio, M., Andaluz, P., Clemente, M., Audi, L., Wollmann, H., Fryklund, L., Parodi, L., Spanish SGA Study Group. The d3/fl-growth hormone (GH) receptor polymorphism does not influence the effect of GH treatment (66 microg/kg per day) or the spontaneous growth in short non-GH-deficient small-for-gestational-age children: results from a two-year controlled prospective study in 170 Spanish patients. J. Clin. Endocr. Metab. 91: 3281-3286, 2006. [PubMed: 16804042] [Full Text: https://doi.org/10.1210/jc.2006-0685]
David, A., Camacho-Hubner, C., Bhangoo, A., Rose, S. J., Miraki-Moud, F., Akker, S. A., Butler, G. E., Ten, S., Clayton, P. E., Clark, A. J. L., Savage, M. O., Metherell, L. A. An intronic growth hormone receptor mutation causing activation of a pseudoexon is associated with a broad spectrum of growth hormone insensitivity phenotypes. J. Clin. Endocr. Metab. 92: 655-659, 2007. [PubMed: 17148568] [Full Text: https://doi.org/10.1210/jc.2006-1527]
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. Nature Genet. 36: 720-724, 2004. [PubMed: 15208626] [Full Text: https://doi.org/10.1038/ng1379]
Duquesnoy, P., Sobrier, M. L., Amselem, S., Goossens, M. Defective membrane expression of human growth hormone (GH) receptor causes Laron-type GH insensitivity syndrome. Proc. Nat. Acad. Sci. 88: 10272-10276, 1991. [PubMed: 1719554] [Full Text: https://doi.org/10.1073/pnas.88.22.10272]
Edery, M., Rozakis-Adcock, M., Goujon, L., Finidori, J., Levi-Meyrueis, C., Paly, J., Djiane, J., Postel-Vinay, M.-C., Kelly, P. A. Lack of hormone binding in COS-7 cells expressing a mutated growth hormone receptor found in Laron dwarfism. J. Clin. Invest. 91: 838-844, 1993. [PubMed: 8450064] [Full Text: https://doi.org/10.1172/JCI116304]
Fang, P., Riedl, S., Amselem, S., Pratt, K. L., Little, B. M., Haeusler, G., Hwa, V., Frisch, H., Rosenfeld, R. G. Primary growth hormone (GH) insensitivity and 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 states. J. Clin. Endocr. Metab. 92: 2223-2231, 2007. [PubMed: 17405847] [Full Text: https://doi.org/10.1210/jc.2006-2624]
Fielder, P. J., Guevara-Aguirre, J., Rosenbloom, A. L., Carlsson, L., Hintz, R. L., Rosenfeld, R. G. Expression of serum insulin-like growth factors, insulin-like growth factor-binding proteins, and the growth hormone-binding protein in heterozygote relatives of Ecuadorian growth hormone receptor deficient patients. J. Clin. Endocr. Metab. 74: 743-750, 1992. [PubMed: 1372321] [Full Text: https://doi.org/10.1210/jcem.74.4.1372321]
Fisker, S., Kristensen, K., Rosenfalck, A. M., Pedersen, S. B., Ebdrup, L., Richelsen, B., Hilsted, J., Christiansen, J. S., Jorgensen, J. O. L. Gene expression of a truncated and the full-length growth hormone (GH) receptor in subcutaneous fat and skeletal muscle in GH-deficient adults: impact of GH treatment. J. Clin. Endocr. Metab. 86: 792-796, 2001. [PubMed: 11158048] [Full Text: https://doi.org/10.1210/jcem.86.2.7250]
Gastier, J. M., Berg, M. A., Vesterhus, P., Reiter, E. O., Francke, U. Diverse deletions in the growth hormone receptor gene cause growth hormone insensitivity syndrome. Hum. Mutat. 16: 323-333, 2000. [PubMed: 11013443] [Full Text: https://doi.org/10.1002/1098-1004(200010)16:4<323::AID-HUMU5>3.0.CO;2-D]
Goddard, A. D., Covello, R., Luoh, S.-M., Clackson, T., Attie, K. M., Gesundheit, N., Rundle, A. C., Wells, J. A., Carlsson, L. M. S. Mutations of the growth hormone receptor in children with idiopathic short stature. New Eng. J. Med. 333: 1093-1098, 1995. [PubMed: 7565946] [Full Text: https://doi.org/10.1056/NEJM199510263331701]
Godowski, P. J., Leung, D. W., Meacham, L. R., Galgani, J. P., Hellmiss, R., Keret, R., Rotwein, P. S., Parks, J. S., Laron, Z., Wood, W. I. Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type dwarfism. Proc. Nat. Acad. Sci. 86: 8083-8087, 1989. [PubMed: 2813379] [Full Text: https://doi.org/10.1073/pnas.86.20.8083]
Greenhalgh, C. J., Rico-Bautista, E., Lorentzon, M., Thaus, A. L., Morgan, P. O., Willson, T. A., Zervoudakis, P., Metcalf, D., Street, I., Nicola, N. A., Nash, A. D., Fabri, L. J., Norstedt, G., Ohlsson, C., Flores-Morales, A., Alexander, W. S., Hilton, D. J. SOCS2 negatively regulates growth hormone action in vitro and in vivo. J. Clin. Invest. 115: 397-406, 2005. [PubMed: 15690087] [Full Text: https://doi.org/10.1172/JCI22710]
Horan, M., Newsway, V., Yasmin, (NI), Lewis, M. D., Easter, T. E., Rees, D. A., Mahto, A., Millar, D. S., Procter, A. M., Scanlon, M. F., Wilkinson, I. B., Hall, I. P., Wheatley, A., Blakey, J., Bath, P. M. W., Cockcroft, J. R., Krawczak, M., Cooper, D. N. Genetic variation at the growth hormone (GH1) and growth hormone receptor (GHR) loci as a risk factor for hypertension and stroke. Hum. Genet. 119: 527-540, 2006. [PubMed: 16572267] [Full Text: https://doi.org/10.1007/s00439-006-0166-5]
Iida, K., Takahashi, Y., Kaji, H., Nose, O., Okimura, Y., Abe, H., Chihara, K. 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. Endocr. Metab. 83: 531-537, 1998. [PubMed: 9467570] [Full Text: https://doi.org/10.1210/jcem.83.2.4601]
Iida, K., Takahashi, Y., Kaji, H., Takahashi, M. O., Okimura, Y., Nose, O., Abe, H., Chihara, K. Functional characterization of truncated growth hormone (GH) receptor-(1-277) causing partial GH insensitivity syndrome with high GH-binding protein. J. Clin. Endocr. Metab. 84: 1011-1016, 1999. [PubMed: 10084588] [Full Text: https://doi.org/10.1210/jcem.84.3.5566]
Jensen, R. B., Vielwerth, S., Larsen, T., Greisen, G., Leffers, H., Juul, A. The presence of the d3-growth hormone receptor polymorphism is negatively associated with fetal growth but positively associated with postnatal growth in healthy subjects. J. Clin. Endocr. Metab. 92: 2758-2763, 2007. [PubMed: 17426087] [Full Text: https://doi.org/10.1210/jc.2007-0176]
Jorge, A. A. L., Marchisotti, F. G., Montenegro, L. R., Carvalho, L. R., Mendonca, B. B., Arnhold, I. J. P. Growth hormone (GH) pharmacogenetics: influence of GH receptor exon 3 retention or deletion on first-year growth response and final height in patients with severe GH deficiency. J. Clin. Endocr. Metab. 91: 1076-1080, 2006. [PubMed: 16291702] [Full Text: https://doi.org/10.1210/jc.2005-2005]
Jorge, A. A., Souza, S. C., Arnhold, I. J., Mendonca, B. B. Poor reproducibility of IGF-I and IGF binding protein-3 generation test in children with short stature and normal coding region of the GH receptor gene. J. Clin. Endocr. Metab. 87: 469-472, 2002. [PubMed: 11836270] [Full Text: https://doi.org/10.1210/jcem.87.2.8191]
Kaji, H., Nose, O., Tajiri, H., Takahashi, Y., Iida, K., Takahashi, T., Okimura, Y., Abe, H., Chihara, K. Novel compound heterozygous mutations of growth hormone (GH) receptor gene in a patient with GH insensitivity syndrome. J. Clin. Endocr. Metab. 82: 3705-3709, 1997. [PubMed: 9360529] [Full Text: https://doi.org/10.1210/jcem.82.11.4344]
Kenth, G., Shao, Z., Cole, D. E. C., Goodyer, C. G. Relationship of the human growth receptor exon 3 genotype with final adult height and bone mineral density. J. Clin. Endocr. Metab. 92: 725-728, 2007. [PubMed: 17090634] [Full Text: https://doi.org/10.1210/jc.2006-1695]
Kranzler, J. H., Rosenbloom, A. L., Martinez, V., Guevara-Aguirre, J. Normal intelligence with severe insulin-like growth factor I deficiency due to growth hormone receptor deficiency: a controlled study in a genetically homogeneous population. J. Clin. Endocr. Metab. 83: 1953-1958, 1998. [PubMed: 9626125] [Full Text: https://doi.org/10.1210/jcem.83.6.4863]
Laron, Z., Klinger, B., Erster, B., Silbergeld, A. Serum GH binding protein activities identifies the heterozygous carriers for Laron type dwarfism. Acta Endocr. 121: 603-608, 1989. [PubMed: 2800930] [Full Text: https://doi.org/10.1530/acta.0.1210603]
Leung, D. W., Spencer, S. A., Cachianes, G., Hammonds, R. G., Collins, C., Henzel, W. J., Barnard, R., Waters, M. J., Wood, W. I. Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature 330: 537-543, 1987. [PubMed: 2825030] [Full Text: https://doi.org/10.1038/330537a0]
Leung, K.-C., Doyle, N., Ballesteros, M., Waters, M. J., Ho, K. K. Y. Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. J. Clin. Endocr. Metab. 85: 4712-4720, 2000. [PubMed: 11134133] [Full Text: https://doi.org/10.1210/jcem.85.12.7017]
Marzullo, P., Buckway, C., Pratt, K. L., Colao, A., Guevara-Aguirre, J., Rosenfeld, R. G. Leptin concentrations in GH deficiency: the effect of GH insensitivity. J. Clin. Endocr. Metab. 87: 540-545, 2002. [PubMed: 11836282] [Full Text: https://doi.org/10.1210/jcem.87.2.8229]
Menon, R. K., Cheng, H., Singh, M. Identification and characterization of single strand DNA-binding protein that represses growth hormone receptor gene expression. Molec. Endocr. 11: 1291-1304, 1997. [PubMed: 9259320] [Full Text: https://doi.org/10.1210/mend.11.9.9967]
Mercado, M., Gonzalez, B., Sandoval, C., Esquenazi, Y., Mier, F., Vargas, G., de los Monteros, A. L. E., Sosa, E. Clinical and biochemical impact of the d3 growth hormone receptor genotype in acromegaly. J. Clin. Endocr. Metab. 93: 3411-3415, 2008. [PubMed: 18611972] [Full Text: https://doi.org/10.1210/jc.2008-0391]
Metherell, L. A., Akker, S. A., Munroe, P. B., Rose, S. J., Caulfield, M., Savage, M. O., Chew, S. L., Clark, A. J. L. Pseudoexon activation as a novel mechanism for disease resulting in atypical growth-hormone insensitivity. Am. J. Hum. Genet. 69: 641-646, 2001. [PubMed: 11468686] [Full Text: https://doi.org/10.1086/323266]
Milward, A., Metherell, L., Maamra, M., Barahona, M. J., Wilkinson, I. R., Camacho-Hubner, C., Savage, M. O., Bidlingmaier, C. M., Clark, A. J. L., Ross, R. J. M., Webb, S. M. Growth hormone (GH) insensitivity syndrome due to a GH receptor truncated after Box1, resulting in isolated failure of STAT 5 signal transduction. J. Clin. Endocr. Metab. 89: 1259-1266, 2004. Note: Erratum: J. Clin. Endocr. Metab. 94: 2674 only, 2009. [PubMed: 15001620] [Full Text: https://doi.org/10.1210/jc.2003-031418]
Pantel, J., Grulich-Henn, J., Bettendorf, M., Strasburger, C. J., Heinrich, U., Amselem, S. Heterozygous nonsense mutation in exon 3 of the growth hormone receptor (GHR) in severe GH insensitivity (Laron syndrome) and the issue of the origin and function of the GHRd3 isoform. J. Clin. Endocr. Metab. 88: 1705-1710, 2003. [PubMed: 12679461] [Full Text: https://doi.org/10.1210/jc.2002-021667]
Pantel, J., Machinis, K., Sobrier, M.-L., Duquesnoy, P., Goossens, M., Amselem, S. Species-specific alternative splice mimicry at the growth hormone receptor locus revealed by the lineage of retroelements during primate evolution: a novel mechanism accounting for protein diversity between and within species. J. Biol. Chem. 275: 18664-18669, 2000. [PubMed: 10764769] [Full Text: https://doi.org/10.1074/jbc.M001615200]
Raz, B., Janner, M., Petkovic, V., Lochmatter, D., Eble, A., Dattani, M. T., Hindmarsh, P. C., Fluck, C. E., Mullis, P. E. Influence of growth hormone (GH) receptor deletion of exon 3 and full-length isoforms on GH response and final height in patients with severe GH deficiency. J. Clin. Endocr. Metab. 93: 974-980, 2008. [PubMed: 18029459] [Full Text: https://doi.org/10.1210/jc.2007-1382]
Rosenbloom, A. L., Guevara-Aguirre, J., Berg, M. A., Francke, U. Stature in Ecuadorians heterozygous for growth hormone receptor gene E180 splice mutation does not differ from that of homozygous normal relatives. J. Clin. Endocr. Metab. 83: 2373-2375, 1998. [PubMed: 9661611] [Full Text: https://doi.org/10.1210/jcem.83.7.4972]
Rosenbloom, A. L., Guevara-Aguirre, J., Rosenfeld, R. G., Fiedler, P. J. The little women of Loja-- growth hormone-receptor deficiency in an inbred population of southern Ecuador. New Eng. J. Med. 323: 1367-1374, 1990. [PubMed: 2233903] [Full Text: https://doi.org/10.1056/NEJM199011153232002]
Rubin, C.-J., Zody, M. C., Eriksson, J., Meadows, J. R. S., Sherwood, E., Webster, M. T., Jiang, L., Ingman, M., Sharpe, T., Ka, S., Hallbook, F., Besnier, F., Carlborg, O., Bed'hom, B., Tixier-Boichard, M., Jensen, P., Siegel, P., Lindblad-Toh, K., Andersson, L. Whole-genome resequencing reveals loci under selection during chicken domestication. Nature 464: 587-591, 2010. [PubMed: 20220755] [Full Text: https://doi.org/10.1038/nature08832]
Sanchez, J. E., Perera, E., Baumbach, L., Cleveland, W. W. Growth hormone receptor mutations in children with idiopathic short stature. J. Clin. Endocr. Metab. 83: 4079-4083, 1998. [PubMed: 9814495] [Full Text: https://doi.org/10.1210/jcem.83.11.5238]
Schreiner, F., Stutte, S., Bartmann, P., Gohlke, B., Woelfle, J. Association of the growth hormone receptor d3-variant and catch-up growth of preterm infants with birth weight of less than 1500 grams. J. Clin. Endocr. Metab. 92: 4489-4493, 2007. [PubMed: 17711923] [Full Text: https://doi.org/10.1210/jc.2007-0956]
Shen, X. Y., Holt, R. I. G., Miell, J. P., Justice, S., Portmann, B., Postel-Vinay, M.-C., Ross, R. J. M. Cirrhotic liver expresses low levels of the full-length and truncated growth hormone receptors. J. Clin. Endocr. Metab. 83: 2532-2538, 1998. [PubMed: 9661639] [Full Text: https://doi.org/10.1210/jcem.83.7.4983]
Shuto, Y., Nakano, T., Sanno, N., Domoto, H., Sugihara, H., Wakabayashi, I. Reduced growth hormone receptor messenger ribonucleic acid in an aged man with chronic malnutrition and growth hormone resistance. J. Clin. Endocr. Metab. 84: 2320-2323, 1999. [PubMed: 10404796] [Full Text: https://doi.org/10.1210/jcem.84.7.5829]
Spencer, S. A., Hammonds, R. G., Henzel, W. J., Rodriguez, H., Waters, M. J., Wood, W. I. Rabbit liver growth hormone receptor and serum binding protein: purification, characterization, and sequence. J. Biol. Chem. 263: 7862-7867, 1988. [PubMed: 3372509]
Stallings-Mann, M. L., Ludwiczak, R. L., Klinger, K. W., Rottman, F. Alternative splicing of exon 3 of the human growth hormone receptor is the result of an unusual genetic polymorphism. Proc. Nat. Acad. Sci. 93: 12394-12399, 1996. [PubMed: 8901592] [Full Text: https://doi.org/10.1073/pnas.93.22.12394]
Stofega, M. R., Herrington, J., Billestrup, N., Carter-Su, C. Mutation of the SHP-2 binding site in growth hormone (GH) receptor prolongs GH-promoted tyrosyl phosphorylation of GH receptor, JAK2, and STAT5B. Molec. Endocr. 14: 1338-1350, 2000. [PubMed: 10976913] [Full Text: https://doi.org/10.1210/mend.14.9.0513]
Takada, D., Ezura, Y., Ono, S., Iino, Y., Katayama, Y., Xin, Y., Wu, L. L., Larringa-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. M., Emi, M. Growth hormone receptor variant (L526I) modifies plasma HDL cholesterol phenotype in familial hypercholesterolemia: intra-familial association study in an eight-generation hyperlipidemic kindred. Am. J. Med. Genet. 121A: 136-140, 2003. [PubMed: 12910492] [Full Text: https://doi.org/10.1002/ajmg.a.20172]
Tiulpakov, A., Rubtsov, P., Dedov, I., Peterkova, V., Bezlepkina, O., Chrousos, G. P., Hochberg, Z. A novel C-terminal growth hormone receptor (GHR) mutation results in impaired GHR-STAT5 but normal STAT-3 signaling. J. Clin. Endocr. Metab. 90: 542-547, 2005. [PubMed: 15536163] [Full Text: https://doi.org/10.1210/jc.2003-2133]
van der Klaauw, A. A., van der Straaten, T., Baak-Pablo, R., Biermasz, N. R., Guchelaar, H.-J., Pereira, A. M., Smit, J. W. A., Romijn, J. A. Influence of the d3-growth hormone (GH) receptor isoform on short-term and long-term treatment response to GH replacement in GH-deficient adults. J. Clin. Endocr. Metab. 93: 2828-2834, 2008. [PubMed: 18397980] [Full Text: https://doi.org/10.1210/jc.2007-2728]
Walker, J. L., Crock, P. A., Behncken, S. N., Rowlinson, S. W., Nicholson, L. M., Boulton, T. J. C., Waters, M. J. A novel mutation affecting the interdomain link region of the growth hormone receptor in a Vietnamese girl, and response to long-term treatment with recombinant human insulin-like growth factor-I and luteinizing hormone-releasing hormone analogue. J. Clin. Endocr. Metab. 83: 2554-2561, 1998. [PubMed: 9661642] [Full Text: https://doi.org/10.1210/jcem.83.7.4954]
Wojcik, J., Berg, M. A., Esposito, N., Geffner, M. E., Sakati, N., Reiter, E. O., Dower, S., Francke, U., Postel-Vinay, M.-C., Finidori, J. Four contiguous amino acid substitutions, identified in patients with Laron syndrome, differently affect the binding affinity and intracellular trafficking of the growth hormone receptor. J. Clin. Endocr. Metab. 83: 4481-4489, 1998. [PubMed: 9851797] [Full Text: https://doi.org/10.1210/jcem.83.12.5357]
Woods, K. A., Fraser, N. C., Postel-Vinay, M.-C., Savage, M. O., Clark, A. J. L. 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. Endocr. Metab. 81: 1686-1690, 1996. [PubMed: 8626815] [Full Text: https://doi.org/10.1210/jcem.81.5.8626815]