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Congenital leptin deficiency is a rare recessively inherited condition due to homozygous mutations in the LEP gene. To date, only nine mutations have been identified in the LEP gene (p.L72S, p.N103K, p.R105W, p.H118L, p.S141C, c.104_106delTCA, c.135del3bp, c.398delG and c.481_482delCT). In this study we present a novel homozygous nonsense mutation...
Context in source publication
Context 1
... early onset obesity was referred to the Obesity & Endocrinology Clinic at the National Research Centre, Cairo, Egypt. He weighed 85 kg, his height was 140 cm and his BMI was 43 kg/m 2 . The parents were first cousins. Pedigree analysis re- vealed 3 similarly affected female sibs two of whom died in early child- hood from recurrent infections (Fig. 1). The patient was born with normal birth weight (3.5 kg). Hyperphagia was noticed since birth. Rapid weight gain and hyperphagia continued and his BMI reached 49.7 kg/m 2 by the age of 13. His sibling was a 3 month old girl, her weight was 9 kg, her length was 64 cm and her BMI was 22.5 kg/m 2 . By the age of 2 years her BMI was 42.5 ...Citations
... Increased rates of mortality at younger ages due to infections in patients with LEP/LEPR deficiency have been reported previously (51,52,58). Leptin is an immune modulator that influences the formation and function of innate and adaptive immune cells (17). ...
... Children with congenital leptin deficiency do not usually manifest growth retardation. [292][293][294][295][296][297][298] Plasma leptin level is usually very low (despite the markedly elevated fat mass), but some mutations in the leptin gene (c.298G→T; p.D100Y) may generate an inactive protein that circulates in plasma (resulting in high leptin levels) being biologically inoperative. ...
The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptor-gamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.
... Increased rates of mortality at younger ages due to infections in patients with LEP/LEPR deficiency have been reported previously (51,52,58). Leptin is an immune modulator that influences the formation and function of innate and adaptive immune cells (17). ...
Context:
Homozygous leptin (LEP) and leptin receptor (LEPR) variants lead to childhood-onset obesity.
Objective:
To present new cases with LEP and LEPR deficiency, report the long-term follow-up of previously described patients, and to define, based on all reported cases in literature, genotype-phenotype relationships.
Methods:
Our cohort included 18 patients (LEP = 11, LEPR = 7), eight of whom had been previously reported. A systematic literature review was conducted in July 2022. 42/47 studies on LEP/LEPR were selected.
Results:
Of 10 new cases, two novel pathogenic variants were identified in LEP (c.16delC) and LEPR (c.40+5G>C). Eleven patients with LEP deficiency received metreleptin, four of whom had been treated for over 20 years. One patient developed loss of efficacy associated with neutralizing antibody development. Of 152 patients, including 134 cases from the literature review in addition to our cases, frameshift variants were the most common (48%) in LEP and missense variants (35%) in LEPR. Patients with LEP deficiency were diagnosed at a younger age (3 (9) vs. 7 (13) years, p = 0.02), and had a higher median BMI SD score (3.1 (2) vs. 2.8 (1) kg/m2, p = 0.02), which was more closely associated with frameshift variants (p = 0.02). Patients with LEP deficiency were more likely to have hyperinsulinemia (p = 0.02).
Conclusion:
Frameshift variants were more common in patients with LEP deficiency whereas missense variants were more common in LEPR deficiency. Patients with LEP deficiency were identified at younger ages, had higher BMI SD scores, and had higher rates of hyperinsulinemia than patients with LEPR deficiency. Eleven patients benefited from long-term metreleptin, with one losing efficacy due to neutralizing antibodies.
... It was also reported that two younger siblings, also with severe obesity and with recurrent respiratory infection, had died. The parents were heterozygous carriers (83). ...
Obesity is a pandemic condition of complex etiology, resulting from the increasing exposition to obesogenic environmental factors combined with genetic susceptibility. In the past two decades, advances in genetic research identified variants of the leptin-melanocortin pathway coding for genes, which are related to the potentiation of satiety and hunger, immune system, and fertility. Here, we review cases of congenital leptin deficiency and the possible beneficial effects of leptin replacement therapy. In summary, the cases presented here show clinical phenotypes of disrupted bodily energy homeostasis, biochemical and hormonal disorders, and abnormal immune response. Some phenotypes can be partially reversed by exogenous administration of leptin. With this review, we aim to contribute to the understanding of leptin gene mutations as targets for obesity diagnostics and treatment strategies.
... In addition, they may have reduced T-cell number and function resulting in increased predisposition to infections and high rates of mortality during childhood (3). After the first report of a frameshift mutation in LEP gene in two severely obese cousins from a consanguineous UK family of Pakistani origin (4), several other patients with frameshift, missense or deletion mutations in LEP gene have been reported (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). These reports of LEP gene mutations have emanated from several countries and especially from regions with high rates of consanguinity (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). ...
... After the first report of a frameshift mutation in LEP gene in two severely obese cousins from a consanguineous UK family of Pakistani origin (4), several other patients with frameshift, missense or deletion mutations in LEP gene have been reported (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). These reports of LEP gene mutations have emanated from several countries and especially from regions with high rates of consanguinity (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). A vast majority (approximately 80%) of about 50 patients described in literature so far come from Central Pakistan (4)(5)(6)(7)(8). ...
Monogenic obesity caused by mutations in one of the several genes involved in the control of hunger and satiety is a rare cause of early-onset obesity (EOO). The most common of the single gene alterations affect the LEP gene resulting in congenital leptin deficiency that manifests as intense hyperphagia, EOO and severe obesity associated hormonal and metabolic alterations. Only eight mutations of LEP gene associated with congenital leptin deficiency in humans have been described. In this study, we report a novel homozygous missense mutation in exon 3 of the LEP gene (chr7:127894610;c.298G>A) resulting in the amino acid substitution of Asparagine for Aspartic acid at codon 100 (p.Asp100Asn) in a 10-month-old infant who presented to us with severe hyperphagia, EOO and had low serum leptin concentrations. Additionally, a homozygous missense variation of unknown significance in exon 11 of BBS1 (Bardet-Biedl syndrome-1) gene (chr11:66291279; G>A; Depth 168x) was detected. Significant abnormalities of lipid parameters were also present in our patient. Both parents were thin built but there was a family history suggestive of EOO in a paternal uncle and a cousin. In conclusion, we report only the second patient from India with a novel mutation of the LEP gene associated with severe obesity.
... Finally, the validity of PolyPhen-2/SIFT/LOFTEE is based on in silico predictions and is thus somehow limited and can hardly replace functional in vitro studies [3,6,7]. The p.Ile35del variant for instance, was not predicted as functionally damaging; however, it is described in Fatima et al. and Saeed et al. to provoke obesity in homozygous conditions [13,16]. We note that other algorithms for predicting the effects of missense variants exist (see, e.g., the programs referenced on https://omictools.com/functional-predictions-category) as well as another (larger) exome and genome sequence database, gnoMAD (http://gnomad.broadinstitute.org/). ...
Background:
Mutations in the leptin gene (LEP) can alter the secretion or interaction of leptin with its receptor, leading to extreme early-onset obesity. The purpose of this work was to estimate the prevalence of heterozygous and homozygous mutations in the leptin gene with the help of the Exome Aggregation Consortium (ExAC) database ( http://exac.broadinstitute.org/about ).
Results:
The ExAC database encompasses exome sequencing data from 60,706 individuals. We searched for listed leptin variants and identified 36 missense, 1 in-frame deletion, and 3 loss-of-function variants. The functional relevance of these variants was assessed by the in silico prediction tools PolyPhen-2, Sorting Intolerant from Tolerant (SIFT), and Loss-Of-Function Transcript Effect Estimator (LOFTEE). PolyPhen-2 predicted 7 of the missense variants to be probably damaging and 10 to be possibly damaging. SIFT predicted 7 of the missense variants to be deleterious. Three loss-of-function variants were predicted by LOFTEE. Excluding double counts, we can summarize 21 variants as potentially damaging. Considering the allele count, we identified 31 heterozygous but no homozygous subjects with at least probably damaging variants. In the ExAC population, the estimated prevalence of heterozygous carriers of these potentially damaging variants was 1:2000. The probability of homozygosity was 1:15,000,000. We furthermore tried to assess the functionality of ExAC-listed leptin variants by applying a knowledge-driven approach. By this approach, additional 6 of the ExAC-listed variants were considered potentially damaging, increasing the number of heterozygous subjects to 58, the prevalence of heterozygosity to 1:1050, and the probability of homozygosity to 1:4,400,000.
Conclusion:
Using exome sequencing data from ExAC, in silico prediction tools and by applying a knowledge-driven approach, we identified 27 probably damaging variants in the leptin gene of 58 heterozygous subjects. With this information, we estimate the prevalence for heterozygosity at 1:1050 corresponding to an incidence of homozygosity of 1:4,400,000 in this large pluriethnic cohort.
... Several mutations have been described in different populations, most frequent in families with high conguinity rates. A consistent change is the mutation N103K; children with this mutation have very low serum leptin levels, suggestive of a functional impact [13][14][15][16]. In studies of leptin deficiency, leptin replacement therapy has had a positive impact by preventing weight gain and obesity; treatment with recombinant human leptin (metreleptin) rapidly normalized eating behavior and resulted in weight loss [17]. ...
... Several mutations have been described in different populations, most frequent in families with high conguinity rates. A consistent change is the mutation N103K; children with this mutation have very low serum leptin levels, suggestive of a functional impact [13][14][15][16]. In studies of leptin deficiency, leptin replacement therapy has had a positive impact by preventing weight gain and obesity; treatment with recombinant human leptin (metreleptin) rapidly normalized eating behavior and resulted in weight loss [17]. ...
Obesity is a chronic disease that has increased alarmingly in recent years. It is considered a risk factor for the development of diseases such as type 2 diabetes, cardiovascular diseases, dyslipidemia, and some types of cancer. Two genetic profiles have been described: monogenic obesity, in which a single gene is mutated, usually leading to loss-of-function or haploinsufficiency, and polygenic obesity, which involves several polymorphic genes with complex interactions between genes and environmental factors. In the latter case, the frequency of polymorphisms can be very high, depending on the population analyzed. In both cases, the genes of interest are associated with changes in body composition through different mechanisms, including hyperphagia, energy expenditure, adipocyte differentiation and lipolysis. However, most studies have analyzed genes associated with obesity in other populations, and the results are often inconsistent, so it is important to study the context of obesity, such as genetics, biochemical biomarkers and environmental factors. Environmental factors include physical activity, nutritional status, and an intake of foods rich in fats and carbohydrates that favor obesity in children. In addition, several chemical compounds have been described as potential endocrine disruptors that increase BMI and produce obesity, and some biological agents can alter the homeostasis of adipose tissue. In this review, we analyzed the genetic and environmental factors that influence obesity, particularly in children.
... Genetic models are beneficial in elucidating the plausible molecular mechanisms involved in the development of certain disease states. However, there were only nine mutations have been identified in the leptin gene in 2014 and mutations were more prevalent in consanguineous marriages [86]. Thus mutations of leptin or leptin receptor rarely occur in humans, implying that they do not actually resemble the human disease state in real life. ...
Metabolic syndrome (MetS) consists of several medical conditions that collectively predict the risk for cardiovascular disease better than the sum of individual conditions. The risk of developing MetS in human depends on synergy of both genetic and environmental factors. Being a multifactorial condition with alarming rate of prevalence nowadays, establishment of appropriate experimental animal models mimicking the disease state in humans is crucial in order to solve the difficulties in evaluating the pathophysiology of MetS in human. This review aims to summarize the underlying mechanisms involved in the pathophysiology of dietary, genetic, and pharmacological models of MetS. Furthermore, we will discuss the usefulness, suitability, pros and cons of these animal models. Even though numerous animal models of MetS have been established, further investigations on the invention of new animal model and clarification of plausible mechanisms are still necessary to confer a better understanding to researchers on the selection of animal models for their studies.
... Two morbidly obese children of Pakistani origin were reported in 1997 to have mutations in the LEP (Montague et al. 1997). Similarly, two novel homozygous mutations in the LEPR were also reported in Pakistani subjects with Mazen et al. (2014) obesity (Saeed et al. 2014b). Mutations in the LEP have been reported from different populations including that of Pakistani origin and are presented in Table 1. ...
Abstract
Leptin protein consists of 167 amino acids, which is mainly secreted from the white adipose tissue. This protein acts on the hypothalamic regions of the brain which control eating behavior, thus playing a significant role in maintaining body’s metabolism. Leptin receptors belong to glycoprotein 130 (gp130) family of cytokine receptors and exist in six isoforms (LEPR a–f), and all the isoforms are encoded by LEPR gene; out of these isoforms, the LEPR-b receptor is the ‘longest form,’ and in most of the cases, mutations in this isoform cause severe obesity. Also, mutations in the leptin gene (LEP) or its receptors gene can lead to obesity. Some biochemical pathways affect the bioactivity of leptin and/or its receptors. To date, eleven pathogenic mutations have been reported in the LEP which are p.L72S, p.N103K, p.R105W, p.H118L, p.S141C, p.W121X c.104_106delTCA, c.135del3bp, c.398delG, c.481_482delCT, and c.163C>T. Different mutations in the LEPR have also been reported as c.2396-1 G>T, c.1675 G>A, p.P316T, etc. In some studies, where leptin was deficient, leptin replacement therapy has shown positive impact by preventing weight gain and obesity.
