RESUMEN
Many clinical and experimental studies have implicated the growth hormone (GH)-insulin-like growth factor (IGF-1) axis with the progression of cancer. The epidemiological finding that patients with Laron syndrome (LS), the best-characterized disease under the spectrum of congenital IGF-1 deficiencies, do not develop cancer is of major scientific and translational relevance. The evasion of LS patients from cancer emphasizes the central role of the GH-IGF-1 system in cancer biology. To identify genes that are differentially expressed in LS and that might provide a biological foundation for cancer protection, we have recently conducted genome-wide profiling of LS patients and normal controls. Analyses were performed on immortalized lymphoblastoid cell lines derived from individual patients. Bioinformatic analyses identified a series of genes that are either over- or under-represented in LS. Differential expression was demonstrated in a number of gene families, including cell cycle, metabolic control, cytokine-cytokine receptor interaction, Jak-STAT and PI3K-AKT signaling, etc. Major differences between LS and controls were also noticed in pathways associated with cell cycle distribution, apoptosis, and autophagy. The identification of novel downstream targets of the GH-IGF-1 network highlights the biological complexity of this hormonal system and sheds light on previously unrecognized mechanistic aspects associated with GH-IGF-1 action in the cancer cell.
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Hormona de Crecimiento Humana , Síndrome de Laron , Neoplasias , Humanos , Hormona del Crecimiento , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Neoplasias/genética , Fosfatidilinositol 3-QuinasasRESUMEN
Laron syndrome (LS) is a rare genetic disorder characterized by low levels of insulin-like growth factor 1 (IGF1) and high levels of growth hormone (GH) due to mutations in the growth hormone receptor gene (GHR). A GHR-knockout (GHR-KO) pig was developed as a model for LS, which displays many of the same features as humans with LS-like transient juvenile hypoglycemia. This study aimed to investigate the effects of impaired GHR signaling on immune functions and immunometabolism in GHR-KO pigs. GHR are located on various cell types of the immune system. Therefore, we investigated lymphocyte subsets, proliferative and respiratory capacity of peripheral blood mononuclear cells (PBMCs), proteome profiles of CD4- and CD4+ lymphocytes and IFN-α serum levels between wild-type (WT) controls and GHR-KO pigs, which revealed significant differences in the relative proportion of the CD4+CD8α- subpopulation and in IFN-α levels. We detected no significant difference in the respiratory capacity and the capacity for polyclonal stimulation in PBMCs between the two groups. But proteome analysis of CD4+ and CD4- lymphocyte populations revealed multiple significant protein abundance differences between GHR-KO and WT pigs, involving pathways related to amino acid metabolism, beta-oxidation of fatty acids, insulin secretion signaling, and oxidative phosphorylation. This study highlights the potential use of GHR-KO pigs as a model for studying the effects of impaired GHR signaling on immune functions.
Asunto(s)
Síndrome de Laron , Receptores de Somatotropina , Humanos , Animales , Porcinos , Receptores de Somatotropina/genética , Receptores de Somatotropina/metabolismo , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Leucocitos Mononucleares/metabolismo , Proteoma , Hormona del Crecimiento/metabolismoRESUMEN
The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway plays a major role in orchestrating cellular interactions, metabolism, growth and aging. Studies from worms to mice showed that downregulated activity of the GH/IGF1 pathway could be beneficial for the extension of lifespan. Laron syndrome (LS) is an inherited autosomal recessive disorder caused by molecular defects of the GH receptor (GHR) gene, leading to congenital IGF1 deficiency. Life-long exposure to minute endogenous IGF1 levels in LS is associated with low stature as well as other endocrine and metabolic deficits. Epidemiological surveys reported that patients with LS have a reduced risk of developing cancer. Studies conducted on LS-derived lymphoblastoid cells led to the identification of a novel link between IGF1 and thioredoxin-interacting protein (TXNIP), a multifunctional mitochondrial protein. TXNIP is highly expressed in LS patients and plays a critical role in cellular redox regulation by thioredoxin. Given that IGF1 affects the levels of TXNIP under various stress conditions, including high glucose and oxidative stress, we hypothesized that the IGF1-TXNIP axis plays an essential role in helping maintain a physiological balance in cellular homeostasis. In this study, we show that TXNIP is vital for the cell fate choice when cells are challenged by various stress signals. Furthermore, prolonged IGF1 treatment leads to the establishment of a premature senescence phenotype characterized by a unique senescence network signature. Combined IGF1/TXNIP-induced premature senescence can be associated with a typical secretory inflammatory phenotype that is mediated by STAT3/IL-1A signaling. Finally, these mechanistic insights might help with the understanding of basic aspects of IGF1-related pathologies in the clinical setting.
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Proteínas Portadoras , Senescencia Celular , Factor I del Crecimiento Similar a la Insulina , Síndrome de Laron , Tiorredoxinas , Animales , Ratones , Proteínas Portadoras/metabolismo , Senescencia Celular/efectos de los fármacos , Senescencia Celular/fisiología , Glucosa/metabolismo , Hormona del Crecimiento/metabolismo , Factor I del Crecimiento Similar a la Insulina/farmacología , Factor I del Crecimiento Similar a la Insulina/fisiología , Síndrome de Laron/metabolismo , Proteínas Mitocondriales/metabolismo , Tiorredoxinas/metabolismo , Humanos , Fibroblastos/efectos de los fármacos , Células 3T3-L1RESUMEN
Normal growth and development in mammals are tightly controlled by numerous genetic factors and metabolic conditions. The growth hormone (GH)-insulin-like growth factor-1 (IGF1) hormonal axis is a key player in the regulation of these processes. Dysregulation of the GH-IGF1 endocrine system is linked to a number of pathologies, ranging from growth deficits to cancer. Laron syndrome (LS) is a type of dwarfism that results from mutation of the GH receptor (GHR) gene, leading to GH resistance and short stature as well as a number of metabolic abnormalities. Of major clinical relevance, epidemiological studies have shown that LS patients do not develop cancer. While the mechanisms associated with cancer protection in LS have not yet been elucidated, genomic analyses have identified a series of metabolic genes that are over-represented in LS patients. We hypothesized that these genes might constitute novel targets for IGF1 action. With a fold-change of 11.09, UDP-glucuronosyltransferase 2B15 (UGT2B15) was the top up-regulated gene in LS. The UGT2B15 gene codes for an enzyme that converts xenobiotic substances into lipophilic compounds and thereby facilitates their clearance from the body. We investigated the regulation of UGT2B15 gene expression by IGF1 and insulin. Both hormones inhibited UGT2B15 mRNA levels in endometrial and breast cancer cell lines. Regulation of UGT2B15 protein levels by IGF1/insulin, however, was more complex and not always correlated with mRNA levels. Furthermore, UGT2B15 expression was dependent on p53 status. Thus, UGT2B15 mRNA levels were higher in cell lines expressing a wild-type p53 compared to cells containing a mutated p53. Animal studies confirmed an inverse correlation between UGT2B15 and p53 levels. In summary, increased UGT2B15 levels in LS might confer upon patient's protection from genotoxic damage.
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Glucuronosiltransferasa/metabolismo , Síndrome de Laron , Neoplasias , Animales , Glucuronosiltransferasa/genética , Glicosiltransferasas/metabolismo , Hormona del Crecimiento/metabolismo , Humanos , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Mamíferos/metabolismo , Neoplasias/metabolismo , ARN Mensajero/genética , Proteína p53 Supresora de Tumor/genética , Uridina DifosfatoRESUMEN
Endometrial cancer is the most common gynecologic malignancy in Western countries. The insulin-like growth factor-1 (IGF1) axis has an important role in endometrial cancer biology and emerged as a promising therapeutic target in oncology. However, there is an urgent need to identify biomarkers that may help in patient stratification and prognosis. Laron syndrome (LS) is a type of dwarfism that results from the mutation of the growth hormone receptor (GHR) gene, leading to congenital IGF1 deficiency. While high circulating IGF1 is regarded as a risk factor in cancer, epidemiological studies have shown that LS patients are protected from cancer development. Recent genome-wide profilings conducted on LS-derived lymphoblastoid cells led to the identification of a series of genes whose over- or under-representation in this condition might be mechanistically linked to cancer protection. The olfactory receptor 5 subfamily H member 2 (OR5H2) was the top downregulated gene in LS, its expression level being 5.8-fold lower than in the control cells. In addition to their typical role in the olfactory epithelium, olfactory receptors (ORs) are expressed in multiple tissues and play non-classical roles in various pathologies, including cancer. The aim of our study was to investigate the regulation of OR5H2 gene expression by IGF1 in endometrial cancer. Data showed that IGF1 and insulin stimulate OR5H2 mRNA and the protein levels in uterine cancer cell lines expressing either a wild-type or a mutant p53. OR5H2 silencing led to IGF1R downregulation, with ensuing reductions in the downstream cytoplasmic mediators. In addition, OR5H2 knockdown reduced the proliferation rate and cell cycle progression. Analyses of olfr196 (the mouse orthologue of OR5H2) mRNA expression in animal models of GHR deficiency or GH overexpression corroborated the human data. In summary, OR5H2 emerged as a novel target for positive regulation by IGF1, with potential relevance in endometrial cancer.
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Neoplasias Endometriales/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Receptores Odorantes/metabolismo , Transducción de Señal/fisiología , Animales , Línea Celular Tumoral , Proliferación Celular , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patología , Neoplasias Endometriales/patología , Femenino , Humanos , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Ratones , Ratones Transgénicos , Receptor IGF Tipo 1/metabolismoRESUMEN
CONTEXT: Growth hormone insensitivity (GHI) in children is characterized by short stature, functional insulin-like growth factor (IGF)-I deficiency, and normal or elevated serum growth hormone (GH) concentrations. The clinical and genetic etiology of GHI is expanding. OBJECTIVE: We undertook genetic characterization of short stature patients referred with suspected GHI and features which overlapped with known GH-IGF-I axis defects. METHODS: Between 2008 and 2020, our center received 149 GHI referrals for genetic testing. Genetic analysis utilized a combination of candidate gene sequencing, whole exome sequencing, array comparative genomic hybridization, and a targeted whole genome short stature gene panel. RESULTS: Genetic diagnoses were identified in 80/149 subjects (54%) with 45/80 (56%) having known GH-IGF-I axis defects (GHR nâ =â 40, IGFALS nâ =â 4, IGFIR nâ =â 1). The remaining 35/80 (44%) had diagnoses of 3M syndrome (nâ =â 10) (OBSL1 nâ =â 7, CUL7 nâ =â 2, and CCDC8 nâ =â 1), Noonan syndrome (nâ =â 4) (PTPN11 nâ =â 2, SOS1 nâ =â 1, and SOS2 nâ =â 1), Silver-Russell syndrome (nâ =â 2) (loss of methylation on chromosome 11p15 and uniparental disomy for chromosome 7), Class 3-5 copy number variations (nâ =â 10), and disorders not previously associated with GHI (nâ =â 9) (Barth syndrome, autoimmune lymphoproliferative syndrome, microcephalic osteodysplastic primordial dwarfism type II, achondroplasia, glycogen storage disease type IXb, lysinuric protein intolerance, multiminicore disease, macrocephaly, alopecia, cutis laxa, and scoliosis syndrome, and Bloom syndrome). CONCLUSION: We report the wide range of diagnoses in 149 patients referred with suspected GHI, which emphasizes the need to recognize GHI as a spectrum of clinical entities in undiagnosed short stature patients. Detailed clinical and genetic assessment may identify a diagnosis and inform clinical management.
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Biomarcadores/análisis , Estatura , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Trastornos del Crecimiento/patología , Síndrome de Laron/patología , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Pruebas Genéticas , Trastornos del Crecimiento/complicaciones , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/metabolismo , Hormona de Crecimiento Humana/metabolismo , Humanos , Lactante , Factor I del Crecimiento Similar a la Insulina/metabolismo , Síndrome de Laron/complicaciones , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Masculino , Pronóstico , Adulto JovenRESUMEN
Recent studies have identified impaired type 2 alveolar epithelial cell (ATII) renewal in idiopathic pulmonary fibrosis (IPF) human organoids and severe fibrosis when ATII is defective in mice. ATIIs function as progenitor cells and require supportive signals from the surrounding mesenchymal cells. The mechanisms by which mesenchymal cells promote ATII progenitor functions in lung fibrosis are incompletely understood. We identified growth hormone receptor (GHR) is mainly expressed in mesenchymal cells, and its expression is substantially decreased in IPF lungs. Higher levels of GHR expression correlated with better lung function in patients with IPF. Profibrotic mesenchymal cells retarded ATII growth and were associated with suppressed vesicular GHR expression. Vesicles enriched with Ghr promote ATII proliferation and diminished pulmonary fibrosis in mesenchymal Ghr-deficient mice. Our findings demonstrate a previously unidentified mesenchymal paracrine signaling coordinated by GHR that is capable of supporting ATII progenitor cell renewal and limiting the severity of lung fibrosis.
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Células Epiteliales Alveolares/fisiología , Fibrosis Pulmonar Idiopática , Animales , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Síndrome de Laron/metabolismo , Pulmón/metabolismo , Ratones , Células Madre/metabolismoRESUMEN
The aim of the study is to find possible explanations for vanishing juvenile hypoglycemia in growth hormone receptor deficiency (GHRD) in human patients and animal models. We reviewed parameters of glucose metabolism in distinct age groups into two human cohorts (Israeli and Ecuadorian) of Laron syndrome (LS) patients, a mouse model (Ghr-KO mouse) and provided additional data for a porcine model (GHR-KO pig). Juvenile hypoglycemia is a common symptom of GHRD and vanishes in adulthood. In the Israeli cohort, developing metabolic syndrome is associated with decreasing insulin sensitivity, insulinopenia and glucose intolerance, and increasing glucose levels with age. In the Ecuadorian patients and both animal models, insulin sensitivity is preserved or even enhanced. Alterations in food intake and energy consumption do not explain the differences in glucose levels; neither is the accumulation of body fat associated with negative effects in the Ecuadorian cohort nor in the animal models. A reduced beta-cell mass and resulting insulin secretory capacity is common and leads to glucose intolerance in Ghr-KO mice, while glucose tolerance is preserved in Ecuadorian patients and the GHR-KO pig. In human patients and the GHR-KO pig, a simultaneous occurrence of normoglycemia with the onset of puberty is reported. Reduced gluconeogenesis in GHRD is discussed to cause juvenile hypoglycemia and a counter-regulatory stimulation of gluconeogenesis can be hypothesized. A coherent study assessing endogenous glucose production and beta-cell capacity in the hypoglycemic and normoglycemic age group is needed. This can be performed in GHR-KO pigs, including castrated animals.
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Hipoglucemia , Síndrome de Laron , Factores de Edad , Animales , Animales Modificados Genéticamente , Estudios de Cohortes , Modelos Animales de Enfermedad , Ecuador/epidemiología , Humanos , Hipoglucemia/epidemiología , Hipoglucemia/etiología , Hipoglucemia/metabolismo , Hipoglucemia/patología , Israel/epidemiología , Síndrome de Laron/complicaciones , Síndrome de Laron/epidemiología , Síndrome de Laron/metabolismo , Síndrome de Laron/patología , Ratones , Ratones Noqueados , Receptores de Somatotropina/genética , Transducción de Señal/fisiología , PorcinosRESUMEN
INTRODUCTION: The growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis has a key role in normal growth and development. Laron syndrome (LS) is a type of dwarfism that results from mutation of the GH receptor, leading to congenital IGF1 deficiency. Epidemiological studies have shown that LS patients are protected from cancer. Genome-wide profiling led to the identification of a series of metabolic genes whose differential expression in LS might be linked to cancer protection. Nephronectin (NPNT) is an intracellular and secreted extracellular matrix protein with important roles in kidney development. NPNT was identified as the top-downregulated gene in LS-derived cells in comparison with ethnic-, age- and gender-matched controls (p-value = 0.0148; fold-change = -3.12 versus controls). NPNT has not been previously linked to the IGF1 signaling pathway. The present study was aimed at evaluating the hypothesis that NPNT is a new target for IGF1 action and that decreased expression of NPNT in LS is correlated with cancer protection. METHODS: Basal and IGF1-stimulated NPNT expression were assessed in LS lymphoblastoid cells as well as in human breast and prostate cancer cells. NPNT silencing experiments were conducted using siRNA methodology. RESULTS: We provide evidence that IGF1 stimulates NPNT expression in LS-derived lymphoblastoids and various cancer cell lines. In addition, we demonstrate that NPNT silencing results in diminished activation of the AKT and ERK1/2 pathways, with ensuing decreases in cellular proliferation. CONCLUSIONS: Our data identified the NPNT gene as a target for IGF1 action. The clinical implications of the functional and physical interactions between NPNT and the IGF1 pathway merit further investigation.
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Proliferación Celular/fisiología , Proteínas de la Matriz Extracelular/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Neoplasias/metabolismo , Transducción de Señal/fisiología , Línea Celular Tumoral , Humanos , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Neoplasias/genéticaRESUMEN
BACKGROUND: We have shown that subjects with Laron syndrome (LS) due to growth hormone receptor deficiency (GHRD) and their relatives have comparable brain structure and function; moreover, the brain of individuals affected with GHRD appears like those of younger people. While the functionally absent growth hormone receptor and the diminished concentrations of the insulin-like growth factor-I have been associated to these findings, the role of the insulin-glucose axis is emerging as an unavoidable consideration when determining the aetiology of these observations. In consequence, we decided to search for the potential and discrete associations between the neurological findings and several parameters of carbohydrate metabolism that might exist in the subjects affected with GHRD. SUBJECTS AND METHODS: Individuals affected with GHRD were compared to relative controls. Besides standard measures of anthropometry, body composition and brain characteristics, the elements of the carbohydrate metabolism (CHO), including glucose, insulin, triacylglycerol and the free insulin growth factor binding protein 1 (IGFBP1) concentrations were determined. In addition, the correlations existing between the parameters of CHO and brain characteristics were established. RESULTS: Besides the phenotypical characteristics of GHRD subjects, including those of brain structure and function, enhanced insulin sensitivity, and other minor, we observed that the insulin-regulated IGFBP1 had a consistent negative correlation with the main elements of the carbohydrate metabolism only in the individuals affected with the disease, and not in their relatives. CONCLUSIONS: When compared to their relatives, subjects with GHRD who lack the counter-regulatory effects of GH on the insulin axis, despite their increased risk factor profile due to obesity and increased body fat percentage, have a healthy and younger looking brain associated to an enhanced and coordinated insulin sensitivity. Furthermore, it was observed that in the GHRD subjects IGFBP1 negatively correlates, in a constant and systematic manner, with the main elements of the CHO metabolism. These observations suggest a direct relationship between an efficient insulin sensitivity and a healthy brain.
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Glucemia/metabolismo , Encéfalo/diagnóstico por imagen , Resistencia a la Insulina , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Insulina/metabolismo , Síndrome de Laron/metabolismo , Obesidad/metabolismo , Triglicéridos/metabolismo , Tejido Adiposo , Adulto , Composición Corporal , Encéfalo/fisiología , Metabolismo de los Hidratos de Carbono , Estudios de Casos y Controles , Familia , Ayuno , Femenino , Neuroimagen Funcional , Humanos , Síndrome de Laron/complicaciones , Síndrome de Laron/diagnóstico por imagen , Síndrome de Laron/genética , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Obesidad/etiología , Periodo Posprandial , Receptores de Somatotropina/genéticaRESUMEN
Laron Syndrome (LS), (OMIM# 262500), a rare recessively inherited disease caused by deletions or mutations of the GH receptor, gene characterized by dwarfism with low or undetectable serum IGF-I in the presence of high serum GH. In addition to dwarfism, the IGF-I deficiency leads to metabolic abnormalities including aberrations in protein biosynthesis and homeostasis. The only available treatment for LS patients is (r)IGF-I administration. The present study was aimed to determine the plasma concentrations of specific amino acids and their metabolites in the blood of untreated and IGF-I-treated LS patients. The study involved a total of 10 LS patients (3 untreated and 7 treated), 2 heterozygote mothers and 3aged subjects. Forty healthy boys and girls served as controls. The analysis of amino acids and their metabolites was performed using the LC-MS/MS analysis and Waters Acc-Q Tag ultra-derivatization kit. Serum IGF-I levels were measured by a one-step sandwich chemiluminescence immunoassay. The results revealed that long-term IGF-I deficiency in LS patients led to abnormal changes in the plasma amino acids metabolism, such as low levels of plasma citrulline, sarcosine and taurine that increased upon IGF-I replacement. The plasma amino acid levels of the heterozygous family members resembled those of the untreated LS patients, whereas the pattern in the 2 double heterozygote sisters previously treated with IGF-I resembled that of the presently IGF-I-treated patients. In addition, plasma É-amino adipic acid levels were elevated in both untreated and IGF-I-treated patients. In summary our data revealed that LS patients, a condition associated with congenital IGF-I deficiency, have an abnormal plasma amino acid metabolism that is partially restored by IGF-I treatment.
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Aminoácidos/metabolismo , Biomarcadores/sangre , Trastornos del Crecimiento/complicaciones , Pérdida Auditiva Sensorineural/complicaciones , Factor I del Crecimiento Similar a la Insulina/deficiencia , Síndrome de Laron/prevención & control , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Factor I del Crecimiento Similar a la Insulina/administración & dosificación , Síndrome de Laron/etiología , Síndrome de Laron/metabolismo , Síndrome de Laron/patología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: The most frequent monogenic causes of growth hormone insensitivity (GHI) include defects in genes encoding the GH receptor itself (GHR), the signal transducer and activator of transcription (STAT5B), the insulin like-growth factor type I (IGF1) and the acid-labile subunit (IGFALS). GHI is characterized by a continuum of mild to severe post-natal growth failure. OBJECTIVE: To characterize the molecular defect in a patient with short stature and partial GHI. PATIENT AND METHODS: The boy was born at term adequate for gestational age from non-consanguineous normal-stature parents. At 2.2â¯years, he presented proportionate short stature (height -2.77 SDS), wide forehead and normal mental development. Whole-exome analysis and functional characterization (site-directed mutagenesis, dual luciferase reporter assay, immunofluorescence and western immunoblot) were performed. RESULTS: Biochemical and endocrinological evaluation revealed partial GH insensitivity with normal stimulated GH peak (7.8â¯ng/mL), undetectable IGF1 and low IGFBP3 levels. Two heterozygous variants in the GH-signaling pathway were found: a novel heterozygous STAT5B variant (c.1896G>T, p.K632N) and a hypomorphic IGFALS variant (c.1642C>T, p.R548W). Functional in vitro characterization demonstrated that p.K632N-STAT5b is an inactivating variant that impairs STAT5b activity through abolished phosphorylation. Remarkably, the patient's immunological evaluation displayed only a mild hypogammaglobulinemia, while a major characteristic of STAT5b deficient patients is severe immunodeficiency. CONCLUSIONS: We reported a novel pathogenic inactivating STAT5b variant, which may be associated with partial GH insensitivity and can present without severe immunological complications in heterozygous state. Our results contribute to expand the spectrum of phenotypes associated to GHI.
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Agammaglobulinemia/genética , Síndrome de Laron/genética , Factor de Transcripción STAT5/genética , Agammaglobulinemia/inmunología , Preescolar , Heterocigoto , Hormona de Crecimiento Humana/metabolismo , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Síndrome de Laron/inmunología , Síndrome de Laron/metabolismo , Síndrome de Laron/fisiopatología , Masculino , Pruebas de Función Hipofisaria , Mutación Puntual , Índice de Severidad de la EnfermedadRESUMEN
The efficacy and safety of IGF-1 therapy in patients with severe primary IGF-I deficiency has been evaluated for more than two decades. Most of the therapeutic experience comes from treating the more severe IGF-I deficient patients, who usually present with a phenotype characteristic of growth hormone receptor deficiency or Laron syndrome. Although most of these patients do not experience enough catchup growth to bring their height into normal range, many individuals achieve an adult height significantly greater than what would have been predicted in the absence of IGF-1 therapy. In the last couple of years a few reports on the benefit of IGF-1 therapy for patients with milder types of IGF-I deficiency have also been published, with variable height outcomes. More short children with prior diagnosis of idiopathic short stature are now being diagnosed with specific molecular defects of the growth hormone/IGF-I axis. Because of this, the clinical spectrum of primary IGF-I deficiency is widening to include many patients with such a milder phenotype, creating a need for well-designed long-term clinical studies evaluating the growth response to growth promoting agents such as rhIGF-1 in these individuals.
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Factor I del Crecimiento Similar a la Insulina/deficiencia , Síndrome de Laron/tratamiento farmacológico , Niño , Preescolar , Hormona de Crecimiento Humana/metabolismo , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Pruebas de Función Hipofisaria , Receptores de Somatotropina/genética , Proteínas Recombinantes , Índice de Severidad de la EnfermedadRESUMEN
The important role of GH in the control of mammalian longevity was first deduced from extended longevity of mice with genetic GH deficiency (GHD) or GH resistance. Mice with isolated GHD (IGHD) due to GHRH or GHRH receptor mutations, combined deficiency of GH, prolactin, and TSH, or global deletion of GH receptors live longer than do their normal siblings. They also exhibit multiple features of delayed and/or slower aging, accompanied by extension of healthspan. The unexpected, remarkable longevity benefit of severe endocrine defects in these animals presumably represents evolutionarily conserved trade-offs among aging, growth, maturation, fecundity, and the underlying anabolic processes. Importantly, the negative association of GH signaling with longevity extends to other mammalian species, apparently including humans. Data obtained in humans with IGHD type 1B, owing to a mutation of the GHRH receptor gene, in the Itabaianinha County, Brazil, provide a unique opportunity to study the impact of severe reduction in GH signaling on age-related characteristics, health, and functionality. Individuals with IGHD are characterized by proportional short stature, doll facies, high-pitched voices, and central obesity. They have delayed puberty but are fertile and generally healthy. Moreover, these IGHD individuals are partially protected from cancer and some of the common effects of aging and can attain extreme longevity, 103 years of age in one case. We think that low, but detectable, residual GH secretion combined with life-long reduction of circulating IGF-1 and with some tissue levels of IGF-1 and/or IGF-2 preserved may account for the normal longevity and apparent extension of healthspan in these individuals.
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Envejecimiento/metabolismo , Enanismo Hipofisario/metabolismo , Hormona del Crecimiento/metabolismo , Síndrome de Laron/metabolismo , Longevidad , Animales , Hormona del Crecimiento/deficiencia , HumanosRESUMEN
Several components of the GH axis are involved in tumor progression, and GH-induced intracellular signaling has been strongly associated with breast cancer susceptibility in genome-wide association studies. In the general population, high IGF-I levels and low IGF-binding protein-3 levels within the normal range are associated with the development of common malignancies, and components of the GH-IGF signaling system exhibit correlations with clinical, histopathological, and therapeutic parameters in cancer patients. Despite promising findings in preclinical studies, anticancer therapies targeting the GH-IGF signaling system have led to disappointing results in clinical trials. There is substantial evidence for some degree of protection against tumor development in several animal models and in patients with genetic defects associated with GH deficiency or resistance. In contrast, the link between GH excess and cancer risk in acromegaly patients is much less clear, and cancer screening in acromegaly has been a highly controversial issue. Recent studies have shown that increased life expectancy in acromegaly patients who attain normal GH and IGF-I levels is associated with more deaths due to age-related cancers. Replacement GH therapy in GH deficiency hypopituitary adults and short children has been shown to be safe when no other risk factors for malignancy are present. Nevertheless, the use of GH in cancer survivors and in short children with RASopathies, chromosomal breakage syndromes, or DNA-repair disorders should be carefully evaluated owing to an increased risk of recurrence, primary cancer, or second neoplasia in these individuals.
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Acromegalia/metabolismo , Hormona del Crecimiento/metabolismo , Hipopituitarismo/metabolismo , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Síndrome de Laron/metabolismo , Neoplasias/metabolismo , Transducción de Señal , Acromegalia/tratamiento farmacológico , Adulto , Animales , Niño , Hormona del Crecimiento/efectos adversos , Hormona del Crecimiento/deficiencia , Humanos , Neoplasias/inducido químicamente , Neoplasias/prevención & controlRESUMEN
Despite increased longevity and resistance to multiple stressors, growth hormone receptor null (GHRKO) mice exhibit severe skeletal impairment. The role of GHR in maintaining osteocyte mitochondrial function is unknown. We found that GHR ablation was detrimental to osteocyte mitochondrial function. In vivo multiphoton microscopy revealed significant reductions of >10% in mitochondrial membrane potential (MMP) in GHRKO osteocytes and reduced mitochondrial volumetric density. Reductions in MMP were accompanied by reductions in glucose transporter-1 levels, steady state ATP, NADH redox index, oxygen consumption rate, and mitochondrial reserve capacity in GHRKO osteocytes. Glycolytic capacity did not differ between control and GHRKO males' osteocytes. However, osteocytes from aged female GHRKO mice exhibited reductions in glycolytic parameters, indicating impairments in glucose metabolism, which may be sex dependent. GHRKO osteocytes exhibited increased levels of cytoplasmic reactive oxygen species (ROS) (both basal and in response to high glucose), insulin-like growth factor-1 (IGF-1), and insulin. Mitochondrial ROS levels were increased and correlated with reduced glutathione in GHRKO osteocytes. Overall, the compromised osteocyte mitochondrial function and responses to metabolic insults strongly correlated with skeletal impairments, suggesting that despite increased life span of the GHRKO mice, skeletal health span is decreased. © 2018 American Society for Bone and Mineral Research.
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Hueso Cortical/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Síndrome de Laron/metabolismo , Mitocondrias/metabolismo , Osteocitos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Hueso Cortical/patología , Factor I del Crecimiento Similar a la Insulina/genética , Síndrome de Laron/genética , Síndrome de Laron/patología , Ratones , Ratones Mutantes , Mitocondrias/genética , Mitocondrias/patología , Osteocitos/patologíaRESUMEN
BACKGROUND: Patients with homozygous intronic pseudoexon GH receptor (GHR) mutations (6Ψ) have growth hormone insensitivity (GHI) (growth failure, IGF1 deficiency and normal/elevated serum GH). We report 9 patients in addition to previously described 11 GHR 6Ψ patients and their responses to rhIGF1 therapy. METHODS: 20 patients (12 males, 11 families, mean age 4.0 ± 2.2 years) were diagnosed genetically in our centre. Phenotypic data and responses to rhIGF1 treatment were provided by referring clinicians. Continuous parametric variables were compared using Student t-test or ANOVA. RESULTS: 10/20 (50%) had typical facial features of GHI, 19/20 (95%) from consanguineous families and 18/20 (90%) of Pakistani origin. At diagnosis, mean height SDS: -4.1 ± 0.95, IGF1 SDS: -2.8 ± 1.4; IGFBP3 SDS: -3.0 ± 2.1 and mean basal and peak GH levels: 11.9 µg/L and 32.9 µg/L, respectively. 1/12 who had IGF1 generation test, responded (IGF1: 132-255 ng/mL). 15/20 (75%; 11M) received rhIGF1 (mean dose: 114 µg/kg twice daily, mean duration: 5.3 ± 2.5 years). Mean baseline height velocity of 4.7 ± 1.1 cm/year increased to 7.4 ± 1.8 cm/year (P = 0.001) during year 1 of therapy. Year 3 mean height SDS (-3.2 ± 1.0) was higher than pre-treatment height SDS (-4.3 ± 0.8) (P = 0.03). Mean cumulative increase in height SDS after year 5 was 1.4 ± 0.9. Difference between target height (TH) SDS and adult or latest height SDS was less than that of TH SDS and pre-treatment height SDS (2.1 ± 1.2 vs 3.0 ± 0.8; P = 0.02). CONCLUSION: In addition to phenotypic heterogeneity in the cohort, there was mismatch between clinical and biochemical features in individual patients with 6Ψ GHR mutations. rhIGF1 treatment improved height outcomes.
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Trastornos del Crecimiento/prevención & control , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/tratamiento farmacológico , Mutación Puntual , Receptores de Somatotropina/agonistas , Receptores de Somatotropina/genética , Estatura/efectos de los fármacos , Niño , Preescolar , Consanguinidad , Resistencia a Medicamentos , Inglaterra , Salud de la Familia , Femenino , Trastornos del Crecimiento/etiología , Homocigoto , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Intrones , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Síndrome de Laron/fisiopatología , Masculino , Pakistán/etnología , Receptores de Somatotropina/metabolismo , Proteínas Recombinantes/uso terapéuticoRESUMEN
Laron syndrome (LS), or primary growth hormone (GH) insensitivity, is the best-characterized entity among the congenital insulin-like growth factor 1 (IGF1) deficiencies. Life-long exposure to minute endogenous IGF1 levels is linked to low stature as well as a number of endocrine and metabolic abnormalities. While elevated IGF1 is correlated with increased cancer incidence, epidemiological studies revealed that patients with LS do not develop tumors. The mechanisms associated with cancer protection in LS are yet to be discovered. Recent genomic analyses identified a series of metabolic genes that are overrepresented in patients with LS. Given the augmented expression of these genes in a low IGF1 milieu, we hypothesized that they may constitute targets for IGF1 action. Thioredoxin-interacting protein (TXNIP) plays a critical role in cellular redox control by thioredoxin. TXNIP serves as a glucose and oxidative stress sensor, being commonly silenced by genetic or epigenetic events in cancer cells. Consistent with its enhanced expression in LS, we provide evidence that TXNIP gene expression is negatively regulated by IGF1. These results were corroborated in animal studies. In addition, we show that oxidative and glucose stresses led to marked increases in TXNIP expression. Supplementation of IGF1 attenuated TXNIP levels, suggesting that IGF1 exerts its antiapoptotic effect via inhibition of TXNIP Augmented TXNIP expression in LS may account for cancer protection in this condition. Finally, TXNIP levels could be potentially useful in the clinic as a predictive or diagnostic biomarker for IGF1R-targeted therapies.
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Proteínas Portadoras/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Síndrome de Laron/metabolismo , Animales , Proteínas Portadoras/genética , Línea Celular , Expresión Génica , Glucosa/metabolismo , Humanos , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Síndrome de Laron/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/prevención & control , Estrés Oxidativo , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Laron syndrome (LS), or primary growth hormone (GH) insensitivity, is a growth disorder that results from mutation of the GH-receptor (GHR) gene leading to congenital insulin-like growth factor-1 (IGF-1) deficiency. Recent epidemiological studies have shown that LS patients are protected from cancer development. Genome-wide profiling identified genes and signaling pathways that are differentially represented in LS patients, and that may contribute to cancer protection. The present study was aimed at evaluating the hypothesis that IGF binding proteins (IGFBPs) are differentially expressed in LS, most probably as a result of low circulating levels of IGF-1. Furthermore, we postulated that IGFBPs might be differentially regulated by oxidative stress in this condition and, therefore, may contribute to cancer evasion. Our results show that IGFBP-3, which is predominantly protective, was highly expressed in LS-derived lymphoblastoid cells in comparison to control cells from the same ethnic group. On the other hand, levels of IGFBP-2, -4, -5, and -6 were diminished in LS patients, as demonstrated by RQ-PCR, Western immunoblots and confocal immunofluorescence. In addition, our data provide evidence for a pattern of IGFBP response to H2O2 treatment that might be associated with distinct expression of apoptosis markers (BCL2, pro-caspase-9, pro-caspase-3) in LS. In summary, differential expression of specific IGFBPs in LS might be correlated with cellular mechanisms underlying cancer protection and, probably, additional phenotypes due to congenital IGF-1 deficiency.
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Apoptosis , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Síndrome de Laron/genética , Linfocitos/metabolismo , Neoplasias/prevención & control , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Síndrome de Laron/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias/genética , Neoplasias/metabolismo , Estrés OxidativoRESUMEN
BACKGROUND/AIMS: Laron syndrome (LS) is an autosomal recessive disease characterized by marked short stature and very low serum IGF-1 and IGFBP-3 levels. This study assessed the clinical and endocrine features alongside determining the growth hormone receptor gene (GHR) mutation in Saudi Arabian patients with LS in order to establish whether or not a genotype/phenotype correlation is evident in this large cohort. SUBJECTS AND METHODS: A total of 40 Saudi Arabian patients with a suspected diagnosis of LS were recruited and subjected to a full clinical and endocrine investigation together with direct sequencing of the coding regions of the GHR gene. RESULTS: GHR mutations were identified in 34 patients from 22 separate nuclear families. All 34 molecularly confirmed patients had the typical clinical and endocrinological manifestations of LS. Eleven different mutations (9 previously unreported) were detected in this cohort of patients, all inherited in an autosomal recessive homozygous form. No genotype/phenotype correlation was apparent. CONCLUSION: The identification of pathogenic mutations causing LS will be of tremendous use for the molecular diagnosis of patients in Saudi Arabia and the region in general, with respect to prevention of this disease in the forms of future carrier testing, prenatal testing, premarital screening and preimplantation genetic diagnosis.