-
Nature Genetics Nov 2015We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of...
We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus <0.01% elsewhere) and in the homozygous state causes Laron syndrome involving short stature. We find that this variant reduces height in heterozygotes by an average of 4.2 cm (-0.64 s.d.). The other variant, in the imprinted KCNQ1 gene (minor allele frequency (MAF) = 7.7% in Sardinia versus <1% elsewhere) reduces height by an average of 1.83 cm (-0.31 s.d.) when maternally inherited. Additionally, polygenic scores indicate that known height-decreasing alleles are at systematically higher frequencies in Sardinians than would be expected by genetic drift. The findings are consistent with selection for shorter stature in Sardinia and a suggestive human example of the proposed 'island effect' reducing the size of large mammals.
Topics: Adult; Aged; Aged, 80 and over; Body Height; Carrier Proteins; Female; Founder Effect; Gene Frequency; Genetic Variation; Genome-Wide Association Study; Genotype; Haplotypes; High-Throughput Nucleotide Sequencing; Humans; Islands; Italy; KCNQ1 Potassium Channel; Laron Syndrome; Longitudinal Studies; Male; Middle Aged; Selection, Genetic; Young Adult
PubMed: 26366551
DOI: 10.1038/ng.3403 -
Clinical Case Reports Nov 2017Glucose and lipid profile together with blood pressure should always be considered for low sera-IGF-1 patients. Even when adulthood is reached, IGF-1 therapy in these...
Glucose and lipid profile together with blood pressure should always be considered for low sera-IGF-1 patients. Even when adulthood is reached, IGF-1 therapy in these patients should be pursued as metabolic and protective cellular effects could be triggered. Real incidence of growth hormone insensitivity is still to be uncovered.
PubMed: 29152285
DOI: 10.1002/ccr3.1193 -
The Israel Medical Association Journal... Jan 2017
Topics: Humans; Insulin-Like Growth Factor I; Laron Syndrome; Neoplasms
PubMed: 28457105
DOI: No ID Found -
Expert Review of Endocrinology &... 2016Adipose tissue (AT) is a well-established target of growth hormone (GH) and is altered in clinical conditions associated with excess, deficiency and absence of GH...
Adipose tissue (AT) is a well-established target of growth hormone (GH) and is altered in clinical conditions associated with excess, deficiency and absence of GH action. Due to the difficulty in collecting AT from clinical populations, genetically modified mice have been useful in better understanding how GH affects this tissue. Recent findings in mice would suggest that the impact of GH on AT is beyond alterations of lipolysis, lipogenesis or proliferation/ differentiation. AT depot-specific alterations in immune cells, extracellular matrix, adipokines, and senescence indicate an expanded role for GH in AT physiology. This mouse data will guide additional studies necessary to evaluate the therapeutic potential and safety of GH for conditions associated with altering AT, such as obesity. In this review, we introduce several relatively new intricacies of GH's effect on AT, focusing on recent studies in mice. Finally, we summarize the clinical implications of these findings.
PubMed: 28435436
DOI: 10.1586/17446651.2016.1147950 -
World Journal of Clinical Cases Dec 2019Laron syndrome (LS) is an autosomal recessive hereditary condition affecting only 1/1000000 births. The cause is associated with mutations in the growth hormone (GH)...
BACKGROUND
Laron syndrome (LS) is an autosomal recessive hereditary condition affecting only 1/1000000 births. The cause is associated with mutations in the growth hormone (GH) receptor (GHR), leading to GH insensitivity. LS patients typically present with severe growth retardation, obesity, and abnormal sexual maturation. Currently, LS diagnosis is performed post-delivery. Therefore, we assessed the efficiency of Pre-implantation Genetic Testing (PGT) coupled with monoplex-polymerase chain reaction (PCR) technology for detecting this monogenic disease in embryos from a couple confirmed as LS heterozygous carriers.
CASE SUMMARY
The couple LS-carriers were confirmed by the presence of a first child born with LS. The couple underwent a standard fertilization (IVF) protocol. DNA was collected from trophectoderm cells from day 5 embryos. Whole genome amplification (WGA) was performed using a Sureplex DNA Amplification System and analyzed by PCR, targeting the deletion of the exons 5 and 6 in the gene as well as PGT by Next-generation Sequencing (Illumina). Eleven embryos were collected and analyzed. 27.3% were the wild type for GHR, 45.5% were heterozygotes, and 18.2% homozygous mutants. One embryo yielded no results. Three 2-embryos transfers were performed; 2 normal homozygous and four heterozygous carriers were selected for transfer. The first two transfers were unsuccessful, whereas the final transfer with two heterozygous embryos resulted in clinical pregnancy. The genomic composition of the fetus was verified, applying the same techniques using amniocytes, extracted after 21 wk of the ongoing pregnancy. The fetus was confirmed as GHR deletion in exon 5-6, carrier. A non-affected baby was born.
CONCLUSION
Here, we present a case demonstrating that using WGA as a template in addition to PCR targeting specific gene regions, exons 5 and 6 on the gene, could identify LS carrier embryos. This provides evidence that WGA and PCR serve as an excellent tool to detect this specific monogenic disease in IVF embryos, thus allowing selection of candidate embryos for transfer successfully when a specific inherited genetic mutation/disease is suspected.
PubMed: 31832405
DOI: 10.12998/wjcc.v7.i23.4029 -
The Journal of Clinical Endocrinology... Jul 2015Ecuadorian subjects with GH receptor deficiency (GHRD) have not developed diabetes, despite obesity.
CONTEXT
Ecuadorian subjects with GH receptor deficiency (GHRD) have not developed diabetes, despite obesity.
OBJECTIVE
We sought to determine the metabolic associations for this phenomenon.
DESIGN
Four studies were carried out: 1) glucose, lipid, adipocytokine concentrations; 2) metabolomics evaluation; 3) metabolic responses to a high-calorie meal; and 4) oral glucose tolerance tests.
SETTING
Clinical Research Institute in Quito, Ecuador.
SUBJECTS
Adults homozygous for the E180 splice mutation of the GH receptor (GHRD) were matched for age, gender, and body mass index with unaffected control relatives (C) as follows: study 1, 27 GHRD and 35 C; study 2, 10 GHRD and 10 C; study 3, seven GHRD and 11 C; and study 4, seven GHRD and seven C.
RESULTS
Although GHRD subjects had greater mean percentage body fat than controls, their fasting insulin, 2-hour blood glucose, and triglyceride levels were lower. The indicator of insulin sensitivity, homeostasis model of assessment 2%S, was greater (P < .0001), and the indicator of insulin resistance, homeostasis model of assessment 2-IR, was lower (P = .0025). Metabolomic differences between GHRD and control subjects were consistent with their differing insulin sensitivity, including postprandial decreases of branched-chain amino acids that were more pronounced in controls. High molecular weight and total adiponectin concentrations were greater in GHRD (P = .0004 and P = .0128, respectively), and leptin levels were lower (P = .02). Although approximately 65% the weight of controls, GHRD subjects consumed an identical high-calorie meal; nonetheless, their mean glucose concentrations were lower, with mean insulin levels one-third those of controls. Results of the 2-hour oral glucose tolerance test were similar.
MAIN OUTCOME MEASURES
Measures of insulin sensitivity, adipocytokines, and energy metabolites.
CONCLUSIONS
Without GH counter-regulation, GHRD is associated with insulin efficiency and obesity. Lower leptin levels, despite higher percentage body fat, suggest that obesity-associated leptin resistance is GH dependent. Elevated adiponectin levels not correlated with percentage body fat indicate that GH signaling is necessary for their typical suppression with obesity.
Topics: Adipokines; Adult; Body Mass Index; Carbohydrate Metabolism; Case-Control Studies; Ecuador; Female; Humans; Insulin Resistance; Laron Syndrome; Lipids; Male; Middle Aged; Obesity; Young Adult
PubMed: 25985182
DOI: 10.1210/jc.2015-1678 -
Science Advances Jun 2021Recent studies have identified impaired type 2 alveolar epithelial cell (ATII) renewal in idiopathic pulmonary fibrosis (IPF) human organoids and severe fibrosis when...
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 expression correlated with better lung function in patients with IPF. Profibrotic mesenchymal cells retarded ATII growth and were associated with suppressed vesicular expression. Vesicles enriched with promote ATII proliferation and diminished pulmonary fibrosis in mesenchymal -deficient mice. Our findings demonstrate a previously unidentified mesenchymal paracrine signaling coordinated by that is capable of supporting ATII progenitor cell renewal and limiting the severity of lung fibrosis.
Topics: Alveolar Epithelial Cells; Animals; Humans; Idiopathic Pulmonary Fibrosis; Laron Syndrome; Lung; Mice; Stem Cells
PubMed: 34108218
DOI: 10.1126/sciadv.abg6005 -
Hormone Research in Paediatrics 2015We report data from the EU Increlex® Growth Forum Database (IGFD) Registry, an ongoing, open-label, observational study monitoring clinical practice use of recombinant...
BACKGROUND/AIMS
We report data from the EU Increlex® Growth Forum Database (IGFD) Registry, an ongoing, open-label, observational study monitoring clinical practice use of recombinant human insulin-like growth factor-1 (rhIGF-1) therapy in children.
METHODS
Safety and effectiveness data on rhIGF-1 treatment of 195 enrolled children with growth failure were collected from December 2008 to September 2013.
RESULTS
Mean ± SD (95% CI) height velocity during first year of rhIGF-1 treatment was 6.9 ± 2.2 cm/year (6.5; 7.2) (n = 144); in prepubertal patients naïve to treatment, this was 7.3 ± 2.0 cm/year (6.8; 7.7) (n = 81). Female sex, younger age at start of rhIGF-1 therapy, and lower baseline height SDS predicted first-year change in height SDS. The most frequent targeted treatment-emergent adverse events (% patients) were hypoglycemia (17.6%, predictors: young age, diagnosis of Laron syndrome, but not rhIGF-1 dose), lipohypertrophy (10.6%), tonsillar hypertrophy (7.4%), injection site reactions (6.4%), and headache (5.9%). Sixty-one serious adverse events (37 related to rhIGF-1 therapy) were reported in 31 patients (16.5%).
CONCLUSION
Safety and effectiveness data on use of rhIGF-1 in a 'real-world' setting were similar to those from controlled randomized trials. Severe growth phenotype and early start of rhIGF-1 improved height response and predicted risk of hypoglycemia.
Topics: Adolescent; Child; Child, Preschool; Databases, Factual; Europe; Female; Growth Disorders; Humans; Insulin-Like Growth Factor I; Male; Recombinant Proteins
PubMed: 25824333
DOI: 10.1159/000371798 -
The Yale Journal of Biology and Medicine Sep 2023Laron syndrome (LS) is a rare autosomal recessively segregating disorder of severe short stature. The condition is characterized by short limbs, delayed puberty,...
Laron syndrome (LS) is a rare autosomal recessively segregating disorder of severe short stature. The condition is characterized by short limbs, delayed puberty, hypoglycemia in infancy, and obesity. Mutations in growth hormone receptor () have been implicated in LS; hence, it is also known as growth hormone insensitivity syndrome (MIM-262500). Here we represent a consanguineous Pakistani family in which three siblings were afflicted with LS. Patients had rather similar phenotypic presentations marked with short stature, delayed bone age, limited extension of elbows, truncal obesity, delayed puberty, childish appearance, and frontal bossing. They also had additional features such as hypo-muscularity, early fatigue, large ears, widely-spaced breasts, and attention deficit behavior, which are rarely reported in LS. The unusual combination of the features hindered a straightforward diagnosis and prompted us to first detect the regions of shared homozygosity and subsequently the disease-causing variant by next generation technologies, like SNP genotyping and exome sequencing. A homozygous pathogenic variant c.508G>C (p.(Asp170His)) in was detected. The variant is known to be implicated in LS, supporting the molecular diagnosis of LS. Also, we present detailed clinical, hematological, and hormonal profiling of the siblings.
Topics: Humans; Laron Syndrome; Mutation; Obesity; Pakistan; Puberty, Delayed; Receptors, Somatotropin
PubMed: 37780997
DOI: 10.59249/TCAA2040 -
Gerontology 2016Growth hormone (GH)-resistant/deficient mice experience improved glucose homeostasis and substantially increased lifespan. Recent evidence suggests that long-lived...
Growth Hormone Receptor Antagonist Transgenic Mice Have Increased Subcutaneous Adipose Tissue Mass, Altered Glucose Homeostasis and No Change in White Adipose Tissue Cellular Senescence.
BACKGROUND
Growth hormone (GH)-resistant/deficient mice experience improved glucose homeostasis and substantially increased lifespan. Recent evidence suggests that long-lived GH-resistant/deficient mice are protected from white adipose tissue (WAT) dysfunction, including WAT cellular senescence, impaired adipogenesis and loss of subcutaneous WAT in old age. This preservation of WAT function has been suggested to be a potential mechanism for the extended lifespan of these mice.
OBJECTIVE
The objective of this study was to examine WAT senescence, WAT distribution and glucose homeostasis in dwarf GH receptor antagonist (GHA) transgenic mice, a unique mouse strain having decreased GH action but normal longevity.
METHODS
18-month-old female GHA mice and wild-type (WT) littermate controls were used. Prior to dissection, body composition, fasting blood glucose as well as glucose and insulin tolerance tests were performed. WAT distribution was determined by weighing four distinct WAT depots at the time of dissection. Cellular senescence in four WAT depots was assessed using senescence-associated β-galactosidase staining to quantify the senescent cell burden, and real-time qPCR to quantify gene expression of senescence markers p16 and IL-6.
RESULTS
GHA mice had a 22% reduction in total body weight, a 33% reduction in lean mass and a 10% increase in body fat percentage compared to WT controls. GHA mice had normal fasting blood glucose and improved insulin sensitivity; however, they exhibited impaired glucose tolerance. Moreover, GHA mice displayed enhanced lipid storage in the inguinal subcutaneous WAT depot (p < 0.05) and a 1.7-fold increase in extra-/intraperitoneal WAT ratio compared to controls (p < 0.05). Measurements of WAT cellular senescence showed no difference between GHA mice and WT controls.
CONCLUSIONS
Similar to other mice with decreased GH action, female GHA mice display reduced age-related lipid redistribution and improved insulin sensitivity, but no change in cellular senescence. The similar abundance of WAT senescent cells in GHA and control mice suggests that any protection against generation of senescent cells afforded by decreased GH action, low insulin-like growth factor 1 and/or improved insulin sensitivity in the GHA mice may be offset by their severe adiposity, since obesity is known to increase senescence.
Topics: Adipocytes, White; Adipogenesis; Animals; Blood Glucose; Cellular Senescence; Female; Glucose Intolerance; Homeostasis; Insulin Resistance; Insulin-Like Growth Factor I; Laron Syndrome; Mice; Mice, Transgenic; Receptors, Somatotropin; Subcutaneous Fat; beta-Galactosidase
PubMed: 26372907
DOI: 10.1159/000439050