The adipocyte-specific hormone leptin, the product of the obese (ob) gene, regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family. In rodents, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadisms. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans.
Leptin resistance and obesity have been related to mutations of the leptin receptor gene in rodents and, recently, in a consanguineous family. The latter mutation results in a receptor lacking transmembrane and intracellular domains. Homozygous and heterozygous individuals with this mutation had serum leptin levels higher than expected, given their BMIs: 600, 670, and 526 ng/ml and 145, 362, 294, 240, and 212 ng/ml, respectively. Their serum leptin was fractionated by gel filtration: >80% was present as a high-molecular size complex vs. 7.5% in the nonmutated sister. Western blot analysis showed a band at 146 kDa reacting specifically with an antibody directed against the leptin receptor ectodomain. In 10 obese control subjects, as in the mutated patients, free leptin levels correlated with BMI (r = 0.70, P = 0.0011) and reflected fat mass, regardless of leptin receptor functioning. In the patients, bound leptin levels correlated with BMI (r = 0.99, P = 0.0002) and were related to the number of mutated alleles. These data demonstrate that the truncated receptor is secreted into blood and binds the majority of serum leptin, markedly increasing bound and total leptin. Free serum leptin was similarly correlated with BMI in the mutated and nonmutated obese individuals, providing evidence that the relationship between BMI and circulating free leptin is preserved in this family. This finding suggests that the leptin receptor itself may not be specifically involved in the control of leptin secretion, and it supports the concept of relative resistance to leptin in common obesity.
Evaluation of GH secretion using pharmacological GH stimulation tests (GHST) remains a current practice, although the reliability of GHST has been questioned, and many pitfalls have been pointed out. We have analyzed all of the 6373 GH stimulation tests that led to the initiation of GH therapy in 3233 children treated in France from [1973][1974][1975][1976][1977][1978][1979][1980][1981][1982][1983][1984][1985][1986][1987][1988][1989]. Tests and GH measurements were performed by individual centers and collected by the Association France-Hypophyse. GH deficiency (GHD) was due to craniospinal irradiation (11%), was due to organic causes or associated with multiple deficiencies (22%), or was considered idiopathic (65%); 2% of the patients were considered non-GHD. Eleven different pharmacological tests were used, and 62 of the 66 theoretical pairs of tests were used at least once. The most frequent combination of tests (ornithine in one instance and insulin in another) was used in 12.7% of patients. The reliability of the GH peak measured by comparing the results of 2 tests in the same patient was poor, as measured by intraclass correlation coefficients below 0.8. Multivariate analysis identified several parameters positively or negatively associated with peak plasma GH: calendar year of initiation of treatment, etiology of GHD, height SD score, bone age SD score, puberty, weight SD score, genetic target height SD score, and the nature of the pharmacological agent used. We believe that several of these factors (weight SD score, genetic target height SD score, and nature of the agent) identify biases in the diagnosis of GHD. We conclude that GHST should be performed with a very limited number of agents, interpreted after the establishment of reference values in age-matched normal children, and associated with other clinical and biochemical parameters for establishing the diagnosis of GHD. (J Clin Endocrinol Metab 82: [2117][2118][2119][2120][2121] 1997) T HE RELIABILITY of pharmacological tests used for evaluating GH secretion have repeatedly been questioned (1-4) for the lack of normal age-related reference values, the use of variable cut-off values with time, the use of different pharmacological stimuli, the dependence on physiological parameters (age, puberty, and body weight), poorly reproducible results, and the use of different laboratory methods and standards for the measurement of plasma GH. Although the diagnosis of GH deficiency (GHD) involves the analyses of height, growth velocity, GH secretion, and GH-dependent plasma proteins and the search for an etiology (4 -7), GH stimulation tests (GHST) are still one of the essential elements of diagnosis. GHST are used to regulate the use of GH in most countries, with the exception of Australia (8). How several potentially confounding factors can influence the results of GHST, the diagnosis, the decision to initiate GH substitutive therapy, and ultimately the results of treatment have not, to our knowledge, been analyzed in a populationbased cohort of tr...
We report on a case of dup(16p) and review previous cases. The triplicated chromosome region leading to this specific syndrome lies in 16p13.1 p13.3. Most of the cases are inherited and the mode of segregation was found to be 3:1 in half of the cases, but these observations might be due to biases. The other chromosomes involved in the translocations as well as the breakpoints in these chromosomes do not appear to be random.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.