-
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 -
Journal of the ASEAN Federation of... 2023Primary growth hormone (GH) resistance or growth hormone insensitivity syndrome, also called Laron syndrome, is a hereditary disease caused by mutations in the GH...
Primary growth hormone (GH) resistance or growth hormone insensitivity syndrome, also called Laron syndrome, is a hereditary disease caused by mutations in the GH receptor or in the post-receptor signaling pathway. This disorder is characterized by postnatal growth failure resembling GH deficiency. Differentiating the two conditions is necessary. We present the cases of two siblings, a 16-year-old female and a 9-year-old male, born from a consanguineous union. Both had normal birth weights with subsequent severe short stature and delayed teeth eruption, with no features suggestive of any systemic illness. Serum insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) were both low. Suspecting GH deficiency, provocative testing with clonidine was done revealing peak growth hormone >40 ng/mL in both patients. In view of low IGF1 and IGFBP3 and high GH on stimulation, IGF1 generation test was done for both siblings, with values supporting the diagnosis of GH insensitivity or Laron syndrome.
Topics: Male; Female; Humans; Adolescent; Child; Laron Syndrome; Siblings; Growth Hormone; Human Growth Hormone; Receptors, Somatotropin
PubMed: 38045665
DOI: 10.15605/jafes.038.02.22 -
Frontiers in Endocrinology 2023The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway emerged in recent years as a key determinant of aging and longevity. Disruption of this... (Review)
Review
The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway emerged in recent years as a key determinant of aging and longevity. Disruption of this network in different animal species, including flies, nematodes and mouse, was consistently associated with an extended lifespan. Epidemiological analyses have shown that patients with Laron syndrome (LS), the best-characterized disease under the umbrella of the congenital IGF1 deficiencies, seem to be protected from cancer. While aging and cancer, as a rule, are considered diametrically opposite processes, modern lines of evidence reinforce the notion that aging and cancer might, as a matter of fact, be regarded as divergent manifestations of identical biochemical and cellular underlying processes. While the effect of individual mutations on lifespan and health span is very difficult to assess, genome-wide screenings identified a number of differentially represented aging- and longevity-associated genes in patients with LS. The present review summarizes recent data that emerged from comprehensive analyses of LS patients and portrays a number of previously unrecognized targets for GH-IGF1 action. Our article sheds light on complex aging and longevity processes, with a particular emphasis on the role of the GH-IGF1 network in these mechanisms.
Topics: Humans; Mice; Animals; Laron Syndrome; Aging; Longevity; Growth Hormone; Human Growth Hormone; Neoplasms
PubMed: 37941907
DOI: 10.3389/fendo.2023.1291812 -
Orphanet Journal of Rare Diseases Oct 2023Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score... (Review)
Review
BACKGROUND
Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care.
OBJECTIVE
To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally.
METHODS
An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD.
RESULTS
As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing.
CONCLUSIONS
To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care. Medical writing support was industry-sponsored.
Topics: Humans; Insulin-Like Growth Factor I; Quality of Life; Laron Syndrome; Dwarfism; Growth Disorders
PubMed: 37805563
DOI: 10.1186/s13023-023-02928-7 -
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 -
Biological & Pharmaceutical Bulletin 2023Growth hormone receptor (GHR)-deficient pigs were generated using the CRISPR/Cas9 system to investigate the involvement of GHR-mediated growth hormone (GH) signaling in...
Growth hormone receptor (GHR)-deficient pigs were generated using the CRISPR/Cas9 system to investigate the involvement of GHR-mediated growth hormone (GH) signaling in androgen-associated gene expression of hepatic drug metabolizing enzymes (DMEs) and drug transporters. We initially confirmed that no wild-type GHR mRNA was present in GHR (GHR-KO) pigs; in addition, as previously reported, those pigs exhibited decreases in body weight and serum insulin-like growth factor-1 concentration and an increase in serum GH concentration compared with the levels in GHR and GHR pigs with a wild-type GHR mRNA. The real-time RT-PCR results on the mRNA levels of hepatic DMEs and drug transporters in the GHR-KO pigs and the pigs with a wild-type GHR mRNA revealed that, among the examined hepatic DMEs, the mRNA levels of CYP1A2, CYP2A19, sulfotransferase (SULT) 1A1, and SULT2A1 were higher in GHR-KO pigs than in the pigs with a wild-type GHR mRNA, whereas the opposite trend was observed for the mRNA level of uridine 5'-diphospho-glucuronosyltransferase 1A6. No such significant differences in the mRNA levels of three hepatic drug transporters including multidrug resistance protein 1 were observed. In addition, the mRNA level of hepatic cut-like homeobox 2 (CUX2), which is expressed in an androgen-dependent manner and associated with the hepatic mRNA expression of several DMEs, was significantly decreased in GHR-KO pigs. The present findings strongly suggest that not only serum androgen but also GHR-mediated GH signaling contributes to the mRNA expression of several DMEs and CUX2, but not transporters, in the pig liver.
Topics: Animals; Swine; Androgens; Laron Syndrome; Membrane Transport Proteins; Fibrinolytic Agents; Gene Expression
PubMed: 37661412
DOI: 10.1248/bpb.b23-00237 -
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 -
BMC Endocrine Disorders Jul 2023Human growth hormone (hGH) plays a crucial role in growth by binding to growth hormone receptor (GHR) in target cells. Binding of GH molecules to their cognate receptors...
BACKGROUND
Human growth hormone (hGH) plays a crucial role in growth by binding to growth hormone receptor (GHR) in target cells. Binding of GH molecules to their cognate receptors triggers downstream signaling pathways leading to the transcription of several genes, including insulin-like growth factor (IGF)-1. Pathogenic variants in the GHR gene can result in structural and functional defects in the GHR protein, leading to Laron Syndrome (LS) with the primary clinical manifestation of short stature. So far, around 100 GHR variants have been reported, mostly biallelic, as causing LS.
CASE PRESENTATION
We report on three siblings from an Iranian consanguineous family who presented with dwarfism. Whole-exome sequencing (WES) was performed on the proband, revealing a novel homozygous missense variant in the GHR gene (NM_000163.5; c.610 T > A, p.(Trp204Arg)) classified as a likely pathogenic variant according to the recommendation of the American College of Medical Genetics (ACMG). Co-segregation analysis was investigated using Sanger sequencing.
CONCLUSIONS
To date, approximately 400-500 LS cases with GHR biallelic variants, out of them 10 patients originating from Iran, have been described in the literature. Given the high rate of consanguineous marriages in the Iranian population, the frequency of LS is expected to be higher, which might be explained by undiagnosed cases. Early diagnosis of LS is very important, as treatment is available for this condition.
Topics: Humans; Receptors, Somatotropin; Laron Syndrome; Iran; Consanguinity; Pedigree; Human Growth Hormone; Dwarfism; Insulin-Like Growth Factor I
PubMed: 37474955
DOI: 10.1186/s12902-023-01388-1 -
Biomolecules Mar 2023Laron 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...
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 (). A -knockout (-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 -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 -KO pigs, which revealed significant differences in the relative proportion of the CD4CD8α 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 -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 -KO pigs as a model for studying the effects of impaired GHR signaling on immune functions.
Topics: Humans; Animals; Swine; Receptors, Somatotropin; Laron Syndrome; Leukocytes, Mononuclear; Proteome; Growth Hormone
PubMed: 37189345
DOI: 10.3390/biom13040597 -
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