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Frontiers in Endocrinology 2021Laron syndrome (LS) is a severe growth disorder caused by gene mutation or post-receptor pathways defect. The clinical features of these patients collected in our...
PURPOSE
Laron syndrome (LS) is a severe growth disorder caused by gene mutation or post-receptor pathways defect. The clinical features of these patients collected in our present study were summarized, gene variants were investigated and further functional verification was carried out.
METHODS
Four patients with LS were collected, their clinical characteristics were summarized, genomic DNA was extracted, and gene was amplified and sequenced. GHR wild type (GHR-WT) and mutant GHR expression plasmids were constructed, and transiently transfected into HepG2 cells and HEK293T cells to observe the subcellular distribution of the GHR protein by immunofluorescence and to determine the expression of GHR and its post-receptor signaling pathway changes by Western blotting.
RESULTS
All of the four patients were male, and the median height was -4.72 SDS. Four gene variants including c.587A>C (p.Y196S), c.766C>T (p.Q256*), c.808A>G (p.I270V) and c.1707-1710del (p.E570Afs*30) were identified, and the latter two were novel mutations. The results of mutant GHR plasmids transfection experiments and immunofluorescence assay showed that the subcellular distribution of GHR-Q256* and GHR-E570Afs*30 mutant proteins in HepG2 and HEK293T cells presented with a unique ring-like pattern, gathering around the nucleus, while GHR-Y196S mutant protein was evenly distributed on HepG2 cell membrane similar to GHR-WT. The GHR protein levels of HepG2 cells transiently transfected with GHR-Y196S, GHR-Q256* and GHR-E570Afs*30 were all significantly lower when compared with cells transfected with GHR-WT (P<0.05). Further mutant GHR post-receptor signal transduction investigation demonstrated that GH induced phosphorylated STAT5 levels of HepG2 cells transfected with three mutant plasmids were all significantly decreased in comparison with that of GHR-WT (P<0.05).
CONCLUSIONS
Two novel gene mutations (I270V and E570Afs*30) were found in our patients with LS. GHR mutations influenced the subcellular distribution and GHR protein levels, then led to the impaired post-receptor signal transduction, suggesting that the mutations contributed to the pathological condition of LS patients.
Topics: Adolescent; Carrier Proteins; Child; Child, Preschool; China; DNA Mutational Analysis; HEK293 Cells; Hep G2 Cells; Humans; Laron Syndrome; Male; Mutation
PubMed: 33912130
DOI: 10.3389/fendo.2021.605736 -
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 -
Hormones (Athens, Greece) 2008Primary or secondary IGF1 deficiency has been implicated in shortening of lifespan. This paper reviews available data on the influence of IGF1 deficiency on lifespan and... (Review)
Review
Primary or secondary IGF1 deficiency has been implicated in shortening of lifespan. This paper reviews available data on the influence of IGF1 deficiency on lifespan and longevity in animals and man. It has been shown that inactivation of the IGF1 gene or of the GH receptor in both invertebrates (C-elegans, flies-Drosphila) and rodents (mice and rats), leading to IGF1 deficiency, prolong life, particularly in females. In man, evaluation of the 2 largest cohorts of patients with Laron syndrome (inactive GH receptor resulting in IGF1 deficiency) in Israel and Ecuador revealed that despite their dwarfism and marked obesity, patients are alive at the ages of 75-78 years, with some having reached even more advanced ages. It is assumed that a major contributing factor is their protection from cancer, a major cause of death in the general population.
Topics: Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Longevity; Neoplasms
PubMed: 18359741
DOI: 10.14310/horm.2002.1111034 -
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 -
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 -
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 -
The American Journal of Case Reports May 2019BACKGROUND Growth hormone insensitivity and reduced levels of insulin-like growth factor-1 (IGF-1) are associated with metabolic syndrome that includes obesity,...
BACKGROUND Growth hormone insensitivity and reduced levels of insulin-like growth factor-1 (IGF-1) are associated with metabolic syndrome that includes obesity, hyperglycemia, type 2 diabetes mellitus, and dyslipidemia. Laron syndrome is a rare autosomal recessive condition associated with insensitivity to growth hormone that results in short stature and metabolic syndrome and is usually diagnosed in childhood. This report is of a 42-year-old Mexican woman with untreated growth hormone insensitivity and diabetic retinopathy, in whom gene sequencing supported the identification of a variant of Laron syndrome. CASE REPORT A 42-year-old Mexican woman with untreated growth hormone insensitivity, metabolic syndrome, and type 2 diabetes mellitus was diagnosed with cataracts, severe retinopathy and hearing loss. She was investigated for genetic causes of reduction in IGF-1. Next-generation sequencing (NGS) showed genetic changes in the growth hormone and IGF-1 axis. The patient's phenotype and genetic changes were consistent with Laron syndrome. CONCLUSIONS The early detection of reduced IGF-1 and identification of the cause of growth hormone insensitivity require international consensus on the approach to diagnosis and treatment methods, including effective IGF-1 replacement therapy. Early diagnosis may reduce the clinical consequences of complications that include short stature the development of metabolic syndrome, type 2 diabetes mellitus, and retinopathy.
Topics: Adult; Diabetic Retinopathy; Drug Hypersensitivity; Female; Growth Hormone; Humans; Insulin-Like Growth Factor I; Laron Syndrome
PubMed: 31086127
DOI: 10.12659/AJCR.913178 -
Molecular Pathology : MP Oct 2001To contribute to the debate about whether growth hormone (GH) and insulin-like growth factor 1 (IGF-1) act independently on the growth process. (Review)
Review
AIM
To contribute to the debate about whether growth hormone (GH) and insulin-like growth factor 1 (IGF-1) act independently on the growth process.
METHODS
To describe growth in human and animal models of isolated IGF-1 deficiency (IGHD), such as in Laron syndrome (LS; primary IGF-1 deficiency and GH resistance) and IGF-1 gene or GH receptor gene knockout (KO) mice.
RESULTS
Since the description of LS in 1966, 51 patients were followed, many since infancy. Newborns with LS are shorter (42-47 cm) than healthy babies (49-52 cm), suggesting that IGF-1 has some influence on intrauterine growth. Newborn mice with IGF-1 gene KO are 30% smaller. The postnatal growth rate of patients with LS is very slow, the distance from the lowest normal centile increasing progressively. If untreated, the final height is 100-136 cm for female and 109-138 cm for male patients. They have acromicia, organomicria including the brain, heart, gonads, genitalia, and retardation of skeletal maturation. The availability of biosynthetic IGF-1 since 1988 has enabled it to be administered to children with LS. It accelerated linear growth rates to 8-9 cm in the first year of treatment, compared with 10-12 cm/year during GH treatment of IGHD. The growth rate in following years was 5-6.5 cm/year.
CONCLUSION
IGF-1 is an important growth hormone, mediating the protein anabolic and linear growth promoting effect of pituitary GH. It has a GH independent growth stimulating effect, which with respect to cartilage cells is possibly optimised by the synergistic action with GH.
Topics: Animals; Embryonic and Fetal Development; Growth; Growth Disorders; Growth Hormone; Humans; Insulin-Like Growth Factor I; Mice; Mice, Knockout; Rats
PubMed: 11577173
DOI: 10.1136/mp.54.5.311 -
The Israel Medical Association Journal... Oct 2004Laron Syndrome, first described in Israel, is a form of dwarfism similar to isolated growth hormone deficiency caused by molecular defects in the GH receptor gene.
BACKGROUND
Laron Syndrome, first described in Israel, is a form of dwarfism similar to isolated growth hormone deficiency caused by molecular defects in the GH receptor gene.
OBJECTIVE
To characterize the molecular defects of the GH-R in Laron syndrome patients followed in our clinic.
METHODS
Of the 63 patients in the cohort, we investigated 31 patients and 32 relatives belonging to several ethnic origins. Molecular analysis of the GH-R gene was performed using the single strand conformation polymorphism and DNA sequencing techniques.
RESULTS
Eleven molecular defects including a novel mutation were found. Twenty-two patients carried mutations in the extracellular domain, one in the transmembrane domain, and 3 siblings with typical Laron syndrome presented a normal GH-R. Of interest are, on one hand, different mutations within the same ethnic groups: W-15X and 5, 6 exon deletion in Jewish-Iraqis, and E180 splice and 5, 6 exon deletion in Jewish-Moroccans; and on the other hand, identical findings in patients from distinct regions: the 785-1 G to T mutation in an Israeli-Druze and a Peruvian patient. A polymorphism in exon 6, Gly168Gly, was found in 15 probands. One typical Laron patient from Greece was heterozygous for R43X in exon 4 and heterozygous for Gly168Gly. In addition, a novel mutation in exon 5: substitution of T to G replacing tyrosine 86 for aspartic acid (Y86D) is described.
CONCLUSIONS
This study demonstrates: a) an increased focal incidence of Laron syndrome in different ethnic groups from our area with a high incidence of consanguinity; and b) a relationship between molecular defects of the GH-R, ethnic group and geographic area.
Topics: Adult; Child; Cohort Studies; Consanguinity; Dwarfism; Humans; Incidence; Israel; Mutation; Polymorphism, Genetic; Receptors, Somatotropin; Sequence Analysis, DNA
PubMed: 15473594
DOI: No ID Found -
Archives of Disease in Childhood Jun 1993Growth curves for children with Laron syndrome were constructed on the basis of repeated measurements made throughout infancy, childhood, and puberty in 24 (10 boys, 14...
Growth curves for children with Laron syndrome were constructed on the basis of repeated measurements made throughout infancy, childhood, and puberty in 24 (10 boys, 14 girls) of the 41 patients with this syndrome investigated in our clinic. Growth retardation was already noted at birth, the birth length ranging from 42 to 46 cm in the 12/20 available measurements. The postnatal growth curves deviated sharply from the normal from infancy on. Both sexes showed no clear pubertal spurt. Girls completed their growth between the age of 16-19 years to a final mean (SD) height of 119 (8.5) cm whereas the boys continued growing beyond the age of 20 years, achieving a final height of 124 (8.5) cm. At all ages the upper to lower body segment ratio was more than 2 SD above the normal mean. These growth curves constitute a model not only for primary, hereditary insulin-like growth factor-I (IGF-I) deficiency (Laron syndrome) but also for untreated secondary IGF-I deficiencies such as growth hormone gene deletion and idiopathic congenital isolated growth hormone deficiency. They should also be useful in the follow up of children with Laron syndrome treated with biosynthetic recombinant IGF-I.
Topics: Age Factors; Body Height; Female; Follow-Up Studies; Growth Disorders; Humans; Infant, Newborn; Insulin-Like Growth Factor I; Male; Syndrome
PubMed: 8333769
DOI: 10.1136/adc.68.6.768