Normal or improved cardiovascular risk factors in IGF-I-deficient adults with growth hormone receptor deficiency.

BACKGROUND: Human subjects with generalized growth hormone (GH) insensitivity due to GH receptor deficiency (GHRD)/Laron syndrome display a very low incidence of insulin resistance, diabetes, and cancer, as well as delayed age-related cognitive decline. However, the risk of cardiovascular disease (CVD) in these subjects is poorly understood. Here, we have assessed cardiovascular function, damage, and risk factors in GHRD subjects and their relatives. METHODS: We measured markers of CVD in two phases: one in a cohort of 30 individuals (GHRD = 16, control relatives = 14) brought to USC (in Los Angeles, CA) and one in a cohort including additional individuals examined in Ecuador (where the subjects live) for a total of 44 individuals (GHRD = 21, control relatives = 23). Data were collected on GHRD and control groups living in similar geographical locations and sharing comparable environmental and socio-economic circumstances. RESULTS: Compared to controls, GHRD subjects displayed lower serum glucose, insulin, blood pressure, smaller cardiac dimensions, similar pulse wave velocity, lower carotid artery intima-media thickness, lower creatinine, and a non-significant but major reduction in the portion of subjects with carotid atherosclerotic plaques (7% GHRDs vs. 36%, Controls p = 0.1333) despite elevated low-density lipoprotein cholesterol levels. CONCLUSION: The current study indicates that individuals with GHRD have normal or improved levels of cardiovascular disease risk factors as compared to their relatives. FUNDING: This study was funded in part by NIH/NIA grant P01 AG034906 to V.D.L.

Growth hormone receptor gene polymorphism. Spontaneous catch up growth in small for gestational age patients.

The growth hormone receptor (GHR) mediates the effect of growth hormone (GH) on linear growth and metabolism. In humans, it exists as two isoforms differing by the retention or exclusion of exon 3; a full-length GHR isoform (GHRfl) and the exon 3-deleted isoform (GHRd3). The genotypic frequency of this polymorphism was analyzed in several studies and in different human populations. However scarce information in Argentinean population is available. Associations between GHRd3 and growth have been reported previously. Some studies have shown that the presence of GHRd3 polymorphism might be a potential variant that improves growth response to recombinant human GH (rhGH) therapy in patients born small for gestational age (SGA), among others. However, over the years the results have been controversial and inconclusive. Based on this, it would be proposed that variants at the genomic level are not completely reflected at the mRNA level. Our aim was to evaluate the genotypic frequencies (%) of the GHR gene polymorphism (GHRfl/GHRfl; GHRfl/GHRd3; GHRd3/GHRd3) in normal Argentinean population (n = 94) and SGA patients (n = 65), and the expression of these polymorphisms at mRNA level in the fetal side of placenta tissues was analyzed. In addition, their association with spontaneous postnatal catch-up growth in SGA patients was also evaluated. In this study, we show a significant increment of compensatory growth in small for gestational age children (SGA) associated to the presence of the GHRd3 allele polymorphism. In addition, the expression of GHR in healthy placentas revealed that no alternative splicing mechanism occurs.

El receptor de la hormona de crecimiento (GHR) media la acción de la hormona de crecimiento (GH) en el crecimiento lineal y el metabolismo. En los seres humanos, existen dos isoformas que difieren en la retención (GHRfl) o exclusión del exón 3 (GHRd3). La frecuencia genotípica de este polimorfismo fue analizada en varios estudios y en diferentes poblaciones. Sin embargo, la información disponible en la población argentina es escasa. Se ha reportado anteriormente asociación entre el polimorfismo GHRd3 y el crecimiento. Varios estudios ha n demostrado que la presencia del polimorfismo GHRd3 podría mejorar, en pacientes nacidos pequeños para la edad gestacional, entre otros, la respuesta a la terapia con GH humana recombinante (rhGH). Sin embargo, a lo largo de los años los resultados han sido controvertidos y no concluyentes. En base a esto, se propondría que las variantes a nivel genómico no se reflejan completamente a nivel del ARNm. Nuestro objetivo fue evaluar la frecuencia genotípica de los polimorfismos del gen del GHR (GHRfl/GHRfl; GHRfl/GHRd3; GHRd3/GHRd3) en la población argentina normal (n = 94) y en niños pequeños para la edad gestacional (n = 65), y se analizó la expresión de estos polimorfismos a nivel de ARNm en la porción fetal de placentas sanas. Además, se evaluó la asociación de este polimorfismo con el crecimiento postnatal espontáneo en pacientes pequeños para la edad gestacional. En este estudio, mostramos un incremento significativo del crecimiento compensatorio en niños pequeños para la edad gestacional asociado a la presencia del polimorfismo del alelo GHRd3. Además, los ensayos de expresión de GHR en placentas sanas revelaron que no se produciría ningún mecanismo de splicing alternativo.

Growth hormone receptor gene polymorphism. Spontaneous catch up growth in small for gestational age patients / Polimorfismo del gen del receptor de la hormona de crecimiento. Crecimiento postnatal espontáneo en niños pequeños para la edad gestacional

Abstract The growth hormone receptor (GHR) mediates the effect of growth hormone (GH) on linear growth and metabolism. In humans, it exists as two isoforms differing by the retention or exclusion of exon 3; a full-length GHR isoform (GHRfl) and the exon 3-deleted isoform (GHRd3). The genotypic frequency of this polymorphism was analyzed in several studies and in different human populations. However scarce information in Argentinean population is available. Associations between GHRd3 and growth have been reported previously. Some studies have shown that the presence of GHRd3 polymorphism might be a potential variant that improves growth response to recombinant human GH (rhGH) therapy in patients born small for gestational age (SGA), among others. However, over the years the results have been controversial and inconclusive. Based on this, it would be proposed that variants at the genomic level are not completely reflected at the mRNA level. Our aim was to evaluate the genotypic frequencies (%) of the GHR gene polymorphism (GHRfl/GHRfl; GHRfl/GHRd3; GHRd3/GHRd3) in normal Argentinean population (n = 94) and SGA patients (n = 65), and the expression of these polymorphisms at mRNA level in the fetal side of placenta tissues was analyzed. In addition, their asso ciation with spontaneous postnatal catch-up growth in SGA patients was also evaluated. In this study, we show a significant increment of compensatory growth in small for gestational age children (SGA) associated to the presence of the GHRd3 allele polymorphism. In addition, the expression of GHR in healthy placentas revealed that no alternative splicing mechanism occurs.

Resumen El receptor de la hormona de creci miento (GHR) media la acción de la hormona de crecimiento (GH) en el crecimiento lineal y el metabolismo. En los seres humanos, existen dos isoformas que difieren en la retención (GHRfl) o exclusión del exón 3 (GHRd3). La frecuencia genotípica de este polimorfismo fue analizada en varios estudios y en diferentes poblaciones. Sin embargo, la información disponible en la población argentina es escasa. Se ha reportado anteriormente asociación entre el polimorfismo GHRd3 y el crecimiento. Varios estudios ha n demostrado que la presencia del polimorfismo GHRd3 podría mejorar, en pacientes nacidos pequeños para la edad gestacional, entre otros, la respuesta a la terapia con GH humana recombinante (rhGH). Sin embargo, a lo largo de los años los resultados han sido con trovertidos y no concluyentes. En base a esto, se propondría que las variantes a nivel genómico no se reflejan completamente a nivel del ARNm. Nuestro objetivo fue evaluar la frecuencia genotípica de los polimorfismos del gen del GHR (GHRfl/GHRfl; GHRfl/GHRd3; GHRd3/GHRd3) en la población argentina normal (n = 94) y en niños pequeños para la edad gestacional (n = 65), y se analizó la expresión de estos polimorfismos a nivel de ARNm en la porción fetal de placentas sanas. Además, se evaluó la asociación de este polimorfismo con el cre cimiento postnatal espontáneo en pacientes pequeños para la edad gestacional. En este estudio, mostramos un incremento significativo del crecimiento compensatorio en niños pequeños para la edad gestacional asociado a la presencia del polimorfismo del alelo GHRd3. Además, los ensayos de expresión de GHR en placentas sanas revelaron que no se produciría ningún mecanismo de splicing alternativo.

Ghrelin-induced Food Intake, but not GH Secretion, Requires the Expression of the GH Receptor in the Brain of Male Mice.

Ghrelin stimulates both GH secretion and food intake. The orexigenic action of ghrelin is mainly mediated by neurons that coexpress agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARH). GH also stimulates food intake and, importantly, ARHAgRP/NPY neurons express GH receptor (GHR). Thus, ghrelin-induced GH secretion may contribute to the orexigenic effect of ghrelin. Here, we investigated the response to ghrelin in male mice carrying GHR ablation specifically in neurons (brain GHR knockout [KO] mice) or exclusively in ARHAgRP/NPY neurons (AgRP GHR KO mice). Although brain GHR KO mice showed normal ghrelin-induced increase in plasma GH levels, these mutants lacked the expected orexigenic response to ghrelin. Additionally, brain GHR KO mice displayed reduced hypothalamic levels of Npy and Ghsr mRNA and did not elicit ghrelin-induced c-Fos expression in the ARH. Furthermore, brain GHR KO mice exhibited a prominent reduction in AgRP fiber density in the ARH and paraventricular nucleus of the hypothalamus (PVH). In contrast, AgRP GHR KO mice showed no changes in the hypothalamic Npy and Ghsr mRNAs and conserved ghrelin-induced food intake and c-Fos expression in the ARH. AgRP GHR KO mice displayed a reduced AgRP fiber density (~16%) in the PVH, but this reduction was less than that observed in brain GHR KO mice (~61%). Our findings indicate that GHR signaling in the brain is required for the orexigenic effect of ghrelin, independently of GH action on ARHAgRP/NPY neurons.

Exon 3-deleted growth hormone receptor isoform is not related to worse bone mineral density or microarchitecture or to increased fracture risk in acromegaly.

PURPOSE: Acromegaly is a cause of secondary osteoporosis and is associated with increased risk of vertebral fractures (VFs). The influence of exon 3-deleted isoform of growth hormone receptor (d3-GHR) on bone microarchitecture has not been studied in acromegaly. AIM: The aim of this study was to analyze the associations between d3-GHR isoform and bone mineral density (BMD), bone microarchitecture, and VFs in acromegaly patients. METHODS: Consecutive acromegaly patients treated at a single reference center were included. BMD was analyzed using dual-energy X-ray absorptiometry (DXA) and bone microarchitecture was analyzed by high-resolution peripheral quantitative computed tomography (HR-pQCT). The presence of moderate to severe VFs was assessed by thoracic and lumbar X-ray. GHR genotyping was analyzed by PCR, and full-length isoform of GHR (fl-GHR) was represented by a 935-bp fragment and d3-GHR by a 532-bp fragment. RESULTS: Eighty-nine patients were included [56 females; median age at diagnosis: 43 years (17-78)]. Disease was uncontrolled in 63% of patients. At least one d3-GHR allele was present in 60% of patients. Frequency of active disease (p = 0.276) and hypogonadism (p = 1.000) was not different between patients with fl-GHR and those with at least one d3-GHR. There was no difference in any DXA or HR-pQCT parameters between patients with fl-GHR and those with d3-GHR. Significant VFs were observed in 14% of patients, but there was no difference in frequency between patients with fl-GHR and those with at least one d3-GHR allele (p = 0.578). CONCLUSIONS: Presence of d3-GHR was not associated with worse BMD or bone microarchitecture or with higher frequency of significant VFs.

Molecular systematics and phylogeography of the endemic Osgood's deermouse Osgoodomys banderanus (Rodentia: Cricetidae) in the lowlands of western Mexico.

Osgoodomys banderanus is a recognized and endemic rodent species of western Mexico, an area known for its high biodiversity and number of endemisms. Phylogeographical relationships within this taxon were analyzed based on mitochondrial (ND3, tRNA-Arginine, ND4L and partial ND4) and nuclear (GHR) nucleotide sequences. We obtained a total of 112 samples from 22 localities, covering the complete distribution of the species. Phylogenetic analyses using Maximum Likelihood and Bayesian inference confirmed that Osgoodomys is a monophyletic group. In addition, phylogenetic and phylogeographic analyses detected three major clades, which do not coincide with the recognized subspecies of O. banderanus. The genetic lineages detected are the western clade (Nayarit, Jalisco and northern Colima), the central clade (Colima, Michoacán, and northern Guerrero) and the eastern clade (central and southern Guerrero). Genetic distances among clades (5-9%) and nucleotide substitutions (30-88) among haplogroups were high, especially in the southern group. Mountain ranges such as the Transmexican Volcanic Belt and the Sierra Madre del Sur, as well as the Balsas River act as geographical barriers for Osgoodomys. Our results suggest the presence of three independent species, which need to be characterized morphologically to confirm our hypothesis.

Direct actions of macronutrient components on goldfish hepatopancreas in vitro to modulate the expression of ghr-I, ghr-II, igf-I and igf-II mRNAs.

In mammals and fish, somatic growth and metabolism are coordinated by the GH-IGF axis, composed of growth hormone (GH), growth hormone receptors I and II (GHR-I and GHR-II), and the insulin-like growth factors I and II (IGF-I and IGF-II). In order to determine if dietary macronutrients regulate the hepatopancreatic expression of ghr-I, ghr-II, igf-I and igf-II independently of circulating GH, organ culture experiments were conducted. Briefly, goldfish hepatopancreas sections were incubated with different doses of glucose; L-tryptophan; oleic acid; linolenic acid (LNA); eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). After two and four hours of treatment, the expression of ghr-I, ghr-II, igf-I and igf-II mRNAs was quantified. We found that glucose and L-tryptophan globally upregulate the mRNA expression of ghr-I; ghr-II; igf-I and igf-II. Duration of exposure, and unsaturation level of fatty acids differentially modulate ghr-I, ghr-II and igf-II mRNA expression. Additionally, we found that fatty acids increase the expression of igf-I depending on incubation time and fatty acid class. In conclusion, here we present evidence for GH-independent, direct effects exerted by dietary macronutrients on GHR and IGF in goldfish hepatopancreas.

Expression, purification and characterization of the authentic form of human growth hormone receptor antagonist G120R-hGH obtained in Escherichia coli periplasmic space.

The human growth hormone receptor antagonist G120R-hGH precludes dimerization of GH and prolactin receptors and consequently JAK/STAT signaling. Some modifications in this antagonist resulted in a drug specific for the GH receptor, called Pegvisomant (Somavert®). However, the original G120R-hGH is usually synthesized in bacterial cytoplasm as inclusion bodies, not being a commercial product. The present work describes the synthesis and characterization of G120R-hGH secreted into bacterial periplasm and obtained with a vector based on a constitutive lambda-PL promoter. This antagonist can be useful for studies aiming at investigating the effects of a simultaneous inhibition of GH and prolactin signaling, as a potential anti-tumoral or anti-diabetic compound. G120R-hGH, synthesized using the W3110 E. coli strain, showed a yield of 1.34 ± 0.24 µg/ml/A600 (∼0.79 mg G120R-hGH/g of wet weight cells) after cultivation at 30 °C up to 3 A600 units and induction at 37 °C, for 6 h, with final 4.3 ± 0.3 A600. A laboratory scale purification was carried out using three chromatographic steps with a total yield of 32%, reaching 98% purity. The obtained protein was characterized by SDS-PAGE, Western Blotting, Mass spectrometry, RP-HPLC, HPSEC and in vitro proliferation bioassay. The proliferation assay, based on Ba/F3-LLP cells, shows that G120R-hGH (100 ng/ml) significantly inhibited (64%) the proliferative action of hGH (1 ng/ml). This is the first time that G120R-hGH is synthesized in bacterial periplasmic space and therefore correctly folded, without the initial methionine. The reasons for a divergent efficacy for antagonizing hGH versus hPRL is currently unknown and deserves further investigation.

Growth hormone receptor exon 3 isoforms may have no importance in the clinical setting of multiethnic Brazilian acromegaly patients.

BACKGROUND: Acromegaly is associated with significant morbidity and increased mortality, but has a variable severity phenotype. The presence of the exon 3-deleted isoform of the growth hormone receptor (d3-GHR) may influence the disease phenotype and treatment outcomes, including the frequency of biochemical discordance after medical treatment. AIMS: The objective of this study was to analyze the influence of the d3-GHR isoform on clinical and biochemical characteristics and in the treatment outcomes of Brazilian multiethnic acromegaly patients. METHODS: We retrospectively analyzed our acromegaly outpatient clinic databank and collected demographic, clinical, biochemical and treatment outcome data from those patients who agreed to participate in the study. A blood sample was collected from all patients, the DNA was extracted and the GHR isoforms were evaluated by PCR, with the full length (fl)-GHR represented by a 935-bp fragment and the d3-GHR represented by a 532-bp fragment. RESULTS: A total of 121 patients were included. Fifty-six patients (46.3 %) were full-length homozygous (fl/fl), 48 (39.7 %) were heterozygous (fl/d3) and 17 (14.0 %) were d3-GHR homozygous (d3/d3). There was no difference between patients homozygous for the fl isoform and those harboring at least one d3-GHR allele in the demographic, clinical and biochemical data or in the treatment outcomes, including somatostatin receptor ligands (SRL) monotherapy, combination therapy with SRL and cabergoline and pegvisomant treatment. There was also no difference between the groups for the frequency of GH and IGF-I discordance after medical treatment. CONCLUSION: GHR exon 3 genotyping appears to have no clinical significance, at least in Brazilian acromegaly patients.

Despite higher body fat content, Ecuadorian subjects with Laron syndrome have less insulin resistance and lower incidence of diabetes than their relatives.

In the present pandemics of obesity and insulin resistant diabetes mellitus (DM), the specific contribution of etiological factors such as shifts in nutritional and exercise patterns, genetic and hormonal, is subject of ongoing research. Among the hormonal factors implicated, we selected obesity-driven insulin resistance for further evaluation. It is known that growth hormone (GH) has profound effects on carbohydrate metabolism. In consequence, we compared the effects of the lack of the counter-regulatory effects of GH, in a group of subjects with GH receptor deficiency (GHRD) due to a mutated GH receptor vs. that of their normal relatives. It was found that, despite their obesity, subjects with GHRD, have diminished incidence of diabetes, lower glucose and insulin concentrations, and lower values of indexes indicative of insulin resistance such as HOMA-IR. The GHRD subjects were also capable of appropriately handling glucose or mixed meal loads despite diminished insulin secretion. These observations allow us to suggest that the association of obesity with increased risk for diabetes appears to be dependent on intact growth hormone signaling.

A half-century of studies of growth hormone insensitivity/Laron syndrome: A historical perspective.

UNLABELLED: A growth hormone (GH) dependent substance responsible for sulfate uptake by costal cartilage of hypophysectomized rats, labeled sulfation factor, was reported in 1957. In 1962 the radioimmunoassay for GH was described. The clinical picture of severe GH deficiency but with high serum concentrations of GH was reported in 3 siblings in 1966 and followed by a 1968 report of 22 patients belonging to 14 consanguineous oriental Jewish families in Israel. Defective sulfation factor generation was demonstrated in 15 of these individuals and in a 1971 report; FFA response to IV GH and growth response to GH injections suggested competitive saturation of peripheral tissue receptors by an abnormal GH. However, studies published in 1973 demonstrated normal fractionation of their circulating GH, and normal binding of GH from 22 patients to various antisera used for radioimmunoassay. In 1976, the Israeli investigators reported that circulating GH from 7 patients reacted normally in the recently developed radioreceptor assay for GH. In 1984, using hepatic microsome pellets, they demonstrated that the defect was a failure of GH binding to receptors. Characterization of the human GH receptor (GHR) gene, reported in 1989, included the initial description of a genetic defect of the GHR in 2 of 9 Israeli patients. At about the same time began the identification in Ecuador of what was to become the largest population of GH insensitivity in the world, ~100 individuals, and the only substantial population with a common mutation of the GH receptor. Treatment studies with recombinant IGF-I began in 1990. Growth response was modest compared to that of GH treated GH deficient subjects. The spectrum of GH insensitivity has expanded beyond GH receptor deficiency to include postreceptor abnormalities: IGF-I gene mutation (1996); IGF-I receptor mutation (2003); signal transducer and activator of transcription 5b mutation (2003); and mutation of the GH-dependent acid labile subunit (2004). CONCLUSION: Rare conditions of GH insensitivity caused by GH receptor and postreceptor abnormalities have provided insights into the processes of growth, body composition, and metabolism.

Effects of somatotrophic axis (GH/GHR) double transgenesis on structural and molecular aspects of the zebrafish immune system.

The development of growth hormone (GH) transgenic fish has been shown to be a promising method to improve growth rates. However, the role of GH is not restricted only to processes involved in growth. Several others physiological processes, including immune function, are impaired due to GH imbalances. Given the importance of generating GH transgenic organisms for aquaculture purposes, it is necessary to develop strategies to reduce or compensate for the collateral effects of GH. We hypothesized that the generation of double transgenic fish that overexpress GH and growth hormone receptor (GHR) in the skeletal muscle could be a possible alternative to compensate for the deleterious effects of GH on the immune system. Specifically, we hypothesized that increased GHR amounts in the skeletal muscle would be able to reduce the level of circulating GH, attenuating the GH signaling on the immune cells while still increasing the growth rate. To test this hypothesis, we evaluated the size of the immune organs, T cell content in the thymus and head kidney, and expression of immune-related genes in double-transgenic fish. Contrary to our expectations, we found that the overexpression of GHR does not decrease the deleterious effect of GH excess on the size of the thymus and head kidney, and in the content of CD3(+) and CD4(+) cells in the thymus and head kidney. Unexpectedly, the control GHR transgenic group showed similar impairments in immune system parameters. These results indicate that GHR overexpression does not reverse the impairments caused by GH and, in addition, could reinforce the damage to the immune functions in GH transgenic zebrafish.

The growth hormone receptor exon 3 polymorphism is not associated with height or metabolic traits in healthy young adults.

CONTEXT: The GHR polymorphisms contribution to the interindividual variability in prenatal and postnatal growth as well as to metabolic traits is controversial. OBJECTIVE: The aim of this study is to analyze the association of the GHRfl/d3 polymorphism with prenatal and postnatal growth and metabolic outcomes in adult life and to compare the genotype distribution in different populations. DESIGN: 385 community healthy subjects followed from birth to adult life (23-25years old) were grouped according to birth size: small-SGA (n=130, 62 males), appropriate-AGA (n=162, 75 males) and large for gestational age-LGA (n=93, 48 males). GHRfl/d3 genotype distribution and its potential association with anthropometric (at birth, childhood and adult life) and metabolic features (in adult life) were analyzed and compared with data obtained from a systematic review of GHRfl/d3 association studies (31 articles). RESULTS: The frequency of the GHR d3/d3 genotype was lower in the LGA (χ2 p=0.01); SGA and AGA subjects exhibited an increased chance of the d3/d3 genotype (OR=3.58; 95%CI: 1.55; 8.24) and (OR=2.39; 95%CI: 1.02; 5.62), respectively. Despite the different prevalence among different birth size groups, in adults, GHRfl/d3 genotype was not associated with height, plasma IGF1 levels or metabolic phenotype and cardiovascular risk. GHRfl/d3 genotype distributions in AGA, SGA and LGA groups were comparable with those found in subjects of European origin but not with those of Asian ancestry. CONCLUSIONS: The GHRd3 genotype was negatively associated with birth size but it was not associated with adult height or weight, plasma IGF1, metabolic phenotype or any marker of increased cardiovascular risk in young adults.

Characterization of pituitary growth hormone and its receptor in the green iguana (Iguana iguana).

Pituitary growth hormone (GH) has been studied in most vertebrate groups; however, only a few studies have been carried out in reptiles. Little is known about pituitary hormones in the order Squamata, to which the green iguana (gi) belongs. In this work, we characterized the hypophysis of Iguana iguana morphologically. The somatotrophs (round cells of 7.6-10 µm containing 250- to 300-nm secretory granules where the giGH is stored) were found, by immunohistochemistry and in situ hybridization, exclusively in the caudal lobe of the pars distalis, whereas the lactotrophs were distributed only in the rostral lobe. A pituitary giGH-like protein was obtained by immuno-affinity chromatography employing a heterologous antibody against chicken GH. giGH showed molecular heterogeneity (22, 44, and 88 kDa by SDS-PAGE/Western blot under non-reducing conditions and at least four charge variants (pIs 6.2, 6.5, 6.9, 7.4) by isoelectric focusing. The pituitary giGH cDNA (1016 bp), amplified by PCR and RACE, encodes a pre-hormone of 218 aa, of which 190 aa correspond to the mature protein and 28 aa to the signal peptide. The giGH receptor cDNA was also partially sequenced. Phylogenetic analyses of the amino acid sequences of giGH and giGHR homologs in vertebrates suggest a parallel evolution and functional relationship between the GH and its receptor.

The E180splice mutation in the GHR gene causing Laron syndrome: witness of a Sephardic Jewish exodus from the Iberian Peninsula to the New World?

Laron syndrome (LS) is a genetic disorder caused by mutations in the growth hormone receptor (GHR) gene. The most frequent GHR mutation is E180splice (rs121909360), which was initially found in an inbred population of Spanish descent in Ecuador and subsequently in Israel, Brazil, Chile, and the United States. The aim of the present study is to determine if the E180splice mutation arose from a common origin. We studied 22 patients with LS from Ecuador, Israel (of Moroccan origin), Brazil, Chile, and the United States (of Mexican origin) who were homozygous for the E180splice mutation and compared them to control individuals for markers surrounding the GHR, intragenic polymorphisms, and Y-chromosome STR. An identical haplotype was found in all but one of the subjects carrying the E180splice mutation: D5S665: 150/150; D5S2082: 192/192; D5S2087: 246/246; rs6179 G/G; and rs6180 C/C. One patient differed from the others only at D5S2082 (168/192). This haplotype is rare (~1%) in control individuals and confirmed that the E180splice-associated haplotype was not derived from independent origins but represented recombination from a common ancestor. The analysis of paternal lineage markers showed that 50% belong to haplogroup R1b (found in Portugal and Spain) and 40% to haplogroups J and E (typical in the Middle East and in Eastern European Jews). The germline E180Splice mutation appears to have originated from a single common ancestor. The presence of Y-chromosome markers associated with Sephardic populations in persons harboring the E180splice mutation provides genetic evidence in support of the historical tracking of the exodus of this specific population.

Extrapituitary growth hormone in the chicken reproductive system.

Increasing evidence shows that growth hormone (GH) expression is not limited to the pituitary, as it can be produced in many other tissues. It is known that growth hormone (GH) plays a role in the control of reproductive tract development. Acting as an endocrine, paracrine and/or autocrine regulator, GH influences proliferation, differentiation and function of reproductive tissues. In this review we substantiate the local expression of GH mRNA and GH protein, as well as the GH receptor (GHR) in both male and female reproductive tract, mainly in the chicken. Locally expressed GH was found to be heterogeneous, with a 17 kDa variant being predominant. GH secretagogues, such as GHRH and TRH co-localize with GH expression in the chicken testis and induce GH release. In the ovarian follicular granulosa cells, GH and GHR are co-expressed and stimulate progesterone production, which was neutralized by a specific GH antibody. Both testicular and follicular cells in primary cultures were able to synthesize and release GH to the culture medium. We also characterized GH and GH mRNA expression in the hen's oviduct and showed that it had 99.6% sequence identity with pituitary GH. Data suggest local reproductive GH may have important autocrine/paracrine effects.

Extrapituitary growth hormone synthesis in humans.

The gene for pituitary growth hormone (GH-N) in man belongs to a multigene locus located at chromosome 17q24.2, which also harbors four additional genes: one for a placental variant of GH-N (named GH-V) and three of chorionic somatommamotropin (CSH) type. Their tandem arrangement from 5' to 3' is: GH-N, CSH-L, CSH-1, GH-V and CSH-2. GH-N is mainly expressed in the pituitary from birth throughout life, while the remaining genes are expressed in the placenta of pregnant women. Pituitary somatotrophs secrete GH into the bloodstream to act at receptor sites in most tissues. GH participates in the regulation of several complex physiological processes, including growth and metabolism. Recently, the presence of GH has been described in several extrapituitary sites, such as neural, ocular, reproductive, immune, cardiovascular, muscular, dermal and skeletal tissues. It has been proposed that GH has an autocrine action in these tissues. While the body of evidence for its presence is constantly growing, research of its possible function and implications lag behind. In this review we highlight the evidence of extrapituitary synthesis of GH in humans.