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Genes Jan 2024Richard Peto's paradox, first described in 1975 from an epidemiological perspective, established an inverse correlation between the probability of developing cancer in... (Review)
Review
Richard Peto's paradox, first described in 1975 from an epidemiological perspective, established an inverse correlation between the probability of developing cancer in multicellular organisms and the number of cells. Larger animals exhibit fewer tumors compared to smaller ones, though exceptions exist. Mice are more susceptible to cancer than humans, while elephants and whales demonstrate significantly lower cancer prevalence rates than humans. How nature and evolution have addressed the issue of cancer in the animal kingdom remains largely unexplored. In the field of medicine, much attention has been devoted to cancer-predisposing genes, as they offer avenues for intervention, including blocking, downregulating, early diagnosis, and targeted treatment. Predisposing genes also tend to manifest clinically earlier and more aggressively, making them easier to identify. However, despite significant strides in modern medicine, the role of protective genes lags behind. Identifying genes with a mild predisposing effect poses a significant challenge. Consequently, comprehending the protective function conferred by genes becomes even more elusive, and their very existence is subject to questioning. While the role of variable expressivity and penetrance defects of the same variant in a family is well-documented for many hereditary cancer syndromes, attempts to delineate the function of protective/modifier alleles have been restricted to a few instances. In this review, we endeavor to elucidate the role of protective genes observed in the animal kingdom, within certain genetic syndromes that appear to act as cancer-resistant/repressor alleles. Additionally, we explore the role of protective alleles in conditions predisposing to cancer. The ultimate goal is to discern why individuals, like Winston Churchill, managed to live up to 91 years of age, despite engaging in minimal physical activity, consuming large quantities of alcohol daily, and not abstaining from smoking.
Topics: Humans; Animals; Mice; Elephants; Alleles; Neoplastic Syndromes, Hereditary; Medicine; Cetacea
PubMed: 38255007
DOI: 10.3390/genes15010118 -
International Journal of Molecular... Nov 2021The growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis is a central player in normal growth and metabolism as well as in a number of pathologies,...
The growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis is a central player in normal growth and metabolism as well as in a number of pathologies, including cancer. The GH-IGF1 hormonal system, in addition, has emerged as a major determinant of lifespan and healthspan. Laron syndrome (LS), the best characterized entity under the spectrum of the congenital IGF1 deficiencies, results from mutation of the GH receptor (GHR) gene, leading to dwarfism, obesity and other defects. Consistent with the key role of IGF1 in cellular proliferation, epidemiological studies have shown that LS patients are protected from cancer development. While reduced expression of components of the GH-IGF1 axis is associated with enhanced longevity in animal models, it is still unknown whether LS is associated with an increased lifespan. MicroRNAs (miRs) are endogenous short non-coding RNAs that regulate the expression of complementary mRNAs. While a number of miRs involved in the regulation of IGF components have been identified, no previous studies have investigated the differential expression of miRs in congenital IGF1 deficiencies. The present study was aimed at identifying miRs that are differentially expressed in LS and that might account for the phenotypic features of LS patients, including longevity. Our genomic analyses provide evidence that miR-132-3p was highly expressed in LS. In addition, we identified SIRT1, a member of the sirtuin family of histone deacetylases, as a target for negative regulation by miR-132-3p. The data was consistent with the notion that low concentrations of IGF1 in LS lead to elevated miR-132-3p levels, with ensuing reduction in SIRT1 gene expression. The impact of the IGF1-miR-132-3p-SIRT1 loop on aging merits further investigation.
Topics: 3' Untranslated Regions; Adult; Case-Control Studies; Cell Line; Cell Proliferation; Female; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Longevity; MicroRNAs; Middle Aged; Sirtuin 1; Up-Regulation
PubMed: 34769292
DOI: 10.3390/ijms222111861 -
FEBS Open Bio Jul 2023Chagas disease (CD) is one of the most devasting parasitic diseases in the Americas, affecting 7-8 million people worldwide. In vitro and in vivo experiments have...
Chagas disease (CD) is one of the most devasting parasitic diseases in the Americas, affecting 7-8 million people worldwide. In vitro and in vivo experiments have demonstrated that growth hormone (GH) serum levels decrease as CD progresses. Interestingly, inactivating mutations in the GH receptor in humans result in Laron syndrome (LS), a clinical entity characterized by increased serum levels of GH and decreased insulin growth factor-1 (IGF-1). The largest cohort of LS subjects lives in the southern provinces of Ecuador. Remarkably, no clinical CD cases have been reported in these individuals despite living in highly endemic areas. In the current ex vivo study, we employed serum from GHR mice, also known as LS mice (a model of GH resistance with high GH and low IGF-1 levels), and serum from bovine GH (bGH) transgenic mice (high GH and IGF-1), to test the effect on Trypanosoma cruzi infection. We infected mouse fibroblast L-cells with T. cruzi (etiological CD infectious agent) and treated them with serum from each mouse type. Treatment with GHR serum (LS mice) significantly decreased L-cell infection by 28% compared with 48% from control wild-type mouse serum (WT). Treatment with bGH mouse serum significantly decreased infection of cells by 41% compared with 54% from WT controls. Our results suggest that high GH and low IGF-1 in blood circulation, as typically seen in LS individuals, confer partial protection against T. cruzi infection. This study is the first to report decreased T. cruzi infection using serum collected from two modified mouse lines with altered GH action (GHR and bGH).
Topics: Mice; Humans; Animals; Cattle; Insulin-Like Growth Factor I; Growth Hormone; Receptors, Somatotropin; Mice, Transgenic; Chagas Disease
PubMed: 37163287
DOI: 10.1002/2211-5463.13627 -
The Indian Journal of Medical Research Nov 2020
Topics: Anemia, Aplastic; Fanconi Anemia; Humans; Laron Syndrome
PubMed: 35345205
DOI: 10.4103/ijmr.IJMR_2317_19 -
Endocrine Connections Aug 2021Animal studies suggest that insulin-like growth factor 1 (IGF1) may influence the function of the hypothalamus-pituitary-testicular axis, especially in childhood, but...
BACKGROUND
Animal studies suggest that insulin-like growth factor 1 (IGF1) may influence the function of the hypothalamus-pituitary-testicular axis, especially in childhood, but the evidence in humans is scanty. Laron syndrome, a human model of IGF1 deficiency, may help to solve this issue.
PURPOSE
This systematic review aims to analyze puberty onset and progression, testicular volume, gonadotropin, and total testosterone serum levels, sperm parameters and fertility, and penile length in patients with Laron syndrome.
METHODS
Specific keywords were used. All data on male patients with Laron syndrome were included.
RESULTS
Seventeen articles matched the inclusion criteria and were entered in the analysis, for a total of 125 male patients. Puberty was absent in 8.9% and delayed in 35.6% of untreated patients of pubertal age. After onset, the duration of the pubertal process was prolonged in 76.9% of untreated patients. The growth spurt was absent in 52.6% and delayed in 31.6% of untreated patients. The testicular volume was small in the two patients who did not receive any treatment. Treatment with IGF1 increased gonadotropin and testosterone serum levels in five out of five patients of pubertal age. No effect was found in four out of four patients younger than 5 years. No study reported data on sperm parameters and fertility. Micropenis occurred in 67.2% of patients.
CONCLUSION AND FUTURE PERSPECTIVES
Delayed puberty is common in patients with Laron syndrome. The growth hormone-IGF1 axis may influence the time of puberty onset. Serum levels of IGF1 should be investigated in children with delayed puberty, scarce progression of testicular growth, and/or micropenis. IGF1 levels might be measured in children with delayed puberty, poor testicular growth, and/or micropenis.
PubMed: 34319907
DOI: 10.1530/EC-21-0252 -
Oxford Medical Case Reports Sep 2021Laron syndrome (LS) is a rare autosomal recessive disorder characterized by dwarfism and typical facial phenotype. This report is the first to present three cases of...
Laron syndrome (LS) is a rare autosomal recessive disorder characterized by dwarfism and typical facial phenotype. This report is the first to present three cases of Laron syndrome affecting three female siblings from Syria. The index case presented at age of 8.5 years with severe short stature: low level of Insulin-like growth factor 1 (IGF-1), elevated levels of fasting and post-stimulation growth hormone (GH), consistent with the diagnosis of Laron syndrome. At the age of 9.5 years, she developed non-autoimmune subclinical hypothyroidism treated with Levothyroxine, then she developed dyslipidemia at the age of 11.3 years. Later, we identified two female siblings of the patient with Laron syndrome. Laron syndrome is a rare genetic disease, reporting of new cases of this rare syndrome must encourage pediatricians to develop high clinical suspicion if faced with patients with very short stature and typical facial features.
PubMed: 34527252
DOI: 10.1093/omcr/omab079 -
Journal of Translational Medicine Feb 2018Laron syndrome is an autosomal disease resulting from mutations in the growth hormone receptor (GHR) gene. The only therapeutic treatment for Laron syndrome is...
BACKGROUND
Laron syndrome is an autosomal disease resulting from mutations in the growth hormone receptor (GHR) gene. The only therapeutic treatment for Laron syndrome is recombinant insulin-like growth factor I (IGF-I), which has been shown to have various side effects. The improved Laron syndrome models are important for better understanding the pathogenesis of the disease and developing corresponding therapeutics. Pigs have become attractive biomedical models for human condition due to similarities in anatomy, physiology, and metabolism relative to humans, which could serve as an appropriate model for Laron syndrome.
METHODS
To further improve the GHR knockout (GHRKO) efficiency and explore the feasibility of precise DNA deletion at targeted sites, the dual-sgRNAs/Cas9 system was designed to target GHR exon 3 in pig fetal fibroblasts (PFFs). The vectors encoding sgRNAs and Cas9 were co-transfected into PFFs by electroporation and GHRKO cell lines were established by single cell cloning culture. Two biallelic knockout cell lines were selected as the donor cell line for somatic cell nuclear transfer for the generation of GHRKO pigs. The genotype of colonies, cloned fetuses and piglets were identified by T7 endonuclease I (T7ENI) assay and sequencing. The GHR expression in the fibroblasts and piglets was analyzed by confocal microscopy, quantitative polymerase chain reaction (q-PCR), western blotting (WB) and immunohistochemical (IHC) staining. The phenotype of GHRKO pigs was recapitulated through level detection of IGF-I and glucose, and measurement of body weight and body size. GHRKO F1 generation were generated by crossing with wild-type pigs, and their genotype was detected by T7ENI assay and sequencing. GHRKO F2 generation was obtained via self-cross of GHRKO F1 pigs. Their genotypes of GHRKO F2 generation was also detected by Sanger sequencing.
RESULTS
In total, 19 of 20 single-cell colonies exhibited biallelic modified GHR (95%), and the efficiency of DNA deletion mediated by dual-sgRNAs/Cas9 was as high as 90% in 40 GHR alleles of 20 single-cell colonies. Two types of GHR allelic single-cell colonies (GHR, GHR) were selected as donor cells for the generation of GHRKO pigs. The reconstructed embryos were transferred into 15 recipient gilts, resulting in 15 GHRKO newborn piglets and 2 fetuses. The GHRKO pigs exhibited slow growth rates and small body sizes. From birth to 13 months old, the average body weight of wild-type pigs varied from 0.6 to 89.5 kg, but that of GHRKO pigs varied from only 0.9 to 37.0 kg. Biochemically, the knockout pigs exhibited decreased serum levels of IGF-I and glucose. Furthermore, the GHRKO pigs had normal reproduction ability, as eighteen GHRKO F1 piglets were obtained via mating a GHRKO pig with wild-type pigs and five GHRKO F2 piglets were obtained by self-cross of F1 generation, indicating that modified GHR alleles can pass to the next generation via germline transmission.
CONCLUSION
The dual-sgRNAs/Cas9 is a reliable system for DNA deletion and that GHRKO pigs conform to typical phenotypes of those observed in Laron patients, suggesting that these pigs could serve as an appropriate model for Laron syndrome.
Topics: Animals; Base Sequence; CRISPR-Associated Protein 9; DNA; Disease Models, Animal; Embryo, Mammalian; Fetus; Fibroblasts; Gene Knockout Techniques; Germ Cells; Growth and Development; Laron Syndrome; Nuclear Transfer Techniques; Receptors, Somatotropin; Swine; RNA, Guide, CRISPR-Cas Systems
PubMed: 29482569
DOI: 10.1186/s12967-018-1409-7 -
The Journal of Clinical Endocrinology... Dec 2023The European Increlex® Growth Forum Database (Eu-IGFD) is an ongoing surveillance registry (NCT00903110) established to collect long-term safety and effectiveness data...
CONTEXT
The European Increlex® Growth Forum Database (Eu-IGFD) is an ongoing surveillance registry (NCT00903110) established to collect long-term safety and effectiveness data on the use of recombinant human insulin-like growth factor-1 (rhIGF-1, mecasermin, Increlex) for the treatment of children/adolescents with severe primary insulin-like growth factor-1 deficiency (SPIGFD).
OBJECTIVE
This analysis of Eu-IGFD data aimed to identify the frequency and predictive factors for hypoglycemia adverse events (AEs) in children treated with rhIGF-1.
METHODS
Data were collected from December 2008 to May 2021. Logistic regression was performed to identify predictive risk factors for treatment-induced hypoglycemia AEs. Odds ratios (ORs) are presented with 95% CIs for each factor.
RESULTS
In total, 306 patients were enrolled in the registry; 84.6% were diagnosed with SPIGFD. Patients who experienced ≥ 1 hypoglycemia AE (n = 80) compared with those with no hypoglycemia AEs (n = 224) had a lower mean age at treatment start (8.7 years vs 9.8 years), a more frequent diagnosis of Laron syndrome (27.5% vs 10.3%), and a history of hypoglycemia (18.8% vs 4.5%). Prior history of hypoglycemia (OR 0.25; 95% CI: [0.11; 0.61]; P = .002) and Laron syndrome diagnosis (OR 0.36; 95% CI: [0.18; 0.72]; P = .004) predicted future hypoglycemia AEs. Total hypoglycemia AEs per patient per treatment year was 0.11 and total serious hypoglycemia AEs per patient per treatment year was 0.01.
CONCLUSION
Hypoglycemia occurs more frequently in patients with prior history of hypoglycemia and/or Laron syndrome compared with patients without these risk factors, and these patients should be carefully monitored for this AE throughout treatment.
Topics: Child; Adolescent; Humans; Laron Syndrome; Hypoglycemia; Longitudinal Studies; Insulin-Like Growth Factor I; Recombinant Proteins; Databases, Factual; Logistic Models
PubMed: 37579214
DOI: 10.1210/clinem/dgad479 -
Genetics and Molecular Biology 2020Laron's syndrome (LS) is a rare genetic disorder characterized by insensitivity to growth hormone (GH). Up to the present time, over 70 mutations of GH receptor (GHR)...
Laron's syndrome (LS) is a rare genetic disorder characterized by insensitivity to growth hormone (GH). Up to the present time, over 70 mutations of GH receptor (GHR) gene have been identified leading to GH/insulin-like growth factor type 1 (IGF1) signaling pathway defect. The number of LS patients worldwide is unknown, as many are probably undiagnosed. We report two sibs from a consanguineous family from Minas Gerais, southeastern Brazil. The parents have three children. The older, a 4-years-old girl was 80.2 cm tall (-5.7 SDS height/age), and the youngest sister, aged 3 years, was 73.2 cm tall (-5.82 SDS height/age). Their clinical and biochemical features are typical of LS patients, such as high serum level of GH and low IGF1 concentrations. A homozygous c.1A>T nucleotide substitution in GHR exon 2 in the probands' samples was identified. Their parents and healthy sister are heterozygous for the same variant that abolishes the translation initiation codon of GHR. This mutation has not been reported in Brazilian patients and was previously associated with an LS phenotype in a single 29-year-old Spanish man. In addition to this case report, we summarize the main characteristics and molecular data of the 21 LS Brazilian patients who have been published to date.
PubMed: 31429861
DOI: 10.1590/1678-4685-GMB-2018-0197 -
International Journal of Biological... 2021Laron syndrome (LS) is an autosomal recessive genetic disease mainly caused by mutations in the human growth hormone receptor () gene. Previous studies have focused on...
Laron syndrome (LS) is an autosomal recessive genetic disease mainly caused by mutations in the human growth hormone receptor () gene. Previous studies have focused on mutant mice, but compared with LS patients, knockout (KO) mice exhibit differential lipid metabolism. To elucidate the relationship between mutation and lipid metabolism, the role of GHR in lipid metabolism was examined in KO pigs and hepatocytes transfected with si. We observed high levels of free fatty acids and hepatic steatosis in KO pigs, which recapitulates the abnormal lipid metabolism in LS patients. RNAseq analysis revealed that genes related to the fatty acid oxidation pathway were significantly altered in KO pigs. AHR, a transcription factor related to lipid metabolism, was significantly downregulated in GHR KO pigs and sitreated human hepatocytes. We found that AHR directly regulated fatty acid oxidation by directly binding to the promoters of ACOX1 and CPT1A and activating their expression. These data indicate that loss of GHR disturbs the ERK-AHR-ACOX1/CPT1A pathway and consequently leads to hepatic steatosis. Our results established AHR as a modulator of hepatic steatosis, thereby providing a therapeutic target for lipid metabolism disorder.
Topics: Animals; Body Weight; Carrier Proteins; Cell Line; Fatty Liver; Female; Gene Expression Regulation; Genotype; Glucose; Glucose Tolerance Test; Hepatocytes; Homeostasis; Humans; Lipid Metabolism; Male; Neoplasm Proteins; Receptors, Aryl Hydrocarbon; Signal Transduction; Swine
PubMed: 34803486
DOI: 10.7150/ijbs.64894