scholarly journals Severe Early-Onset Obesity in Three Adult Patients Harboring Inactivating Mutations of the Leptin Receptor Gene

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A37-A37
Author(s):  
Carolina Marques Chaves ◽  
Teresa Kay ◽  
Joao Anselmo
Keyword(s):  
Early Onset ◽  
Leptin Receptor ◽  
Reference Range ◽  
Receptor Gene ◽  
Pubertal Development ◽  
Genetic Diagnosis ◽  
The Body ◽  
Homozygous Mutation ◽  
Genetic Sequencing ◽  
Lepr Gene

Abstract Background: Leptin is secreted by white adipocytes in response to fat storage and binds to leptin receptors (LEPR) expressed all over the body particularly in hypothalamic neurons. This hormone regulates several physiologic functions including energy expenditure and appetite. Clinical Case: We describe the clinical and hormonal findings in 3 adult brothers with body mass index (BMI) of 36.7, 50.7, and 46.1 kg/m2, respectively. There is no history of consanguinity in the family and none of the patients exhibited dysmorphic features. A rapid weight gain was noticed during their first few months of life, associated with permanent hyperphagia. At 2 years old, their BMI was already above 25 kg/m2 (> +3SD), and at 10 years old, it was over 40 kg/m2 (> +3SD). The linear growth was within the expected target heights for their parents. They did not seem to present cognitive impairment. The pubertal development began at 16 to 18 years old, and since then they maintained levels and FSH and LH above the upper limit of normal (15.6±3.7mUI/mL and 12.3±2.2mUI/mL, reference range 1.5–12.4 and 1.7–8.6, respectively), but with normal sexual steroids (estradiol 36.4±16.1pg/mL and total testosterone 445±401ng/dL, reference range 11–44 and 249–836, respectively). The thyroid function was normal and none of the patients suffered from dyslipidemia or diabetes, despite high serum insulin levels 26.4±15.8 mU/L (normal 5–10). Genetic sequencing identified a homozygous mutation of the leptin receptor gene in the 3 brothers: c.2357T> C, p. (Leu786Pro). Their parents were heterozygous for the mutation as well as the patients’ daughters. Homozygous carriers of the mutation presented a significantly higher BMI than their heterozygous family members, 44.5±7.1 Kg/m2 vs 32.2±1.7 Kg/m2 (p=0.023), a significantly increased leptin levels, 80±36.4 ng/ml vs 26.3±9.3 ng/ml (p=0.028), and significantly higher weight, 134.6±16.9 vs 89.2±15,2 kg (p=0.021), respectively. Women had higher BMI than men (42.0 ±12.2 Kg/m2 vs 37.9±7.5 Kg/m2, p=0.496) and also higher percentage of fat (46.4±3.1% vs 34.9±6.8%, p=0.108). Serum levels of leptin in homozygous patients were not significantly higher than those measured in 10 patients with adult-onset morbid obesity, 80± 36.4 ng/ml vs 53.8±24.1 ng/ml, respectively (p=0.149). Therefore, serum leptin is not a useful discriminative maker of LEPR gene mutations. Conclusion: Patients with severe early-onset obesity should have a genetic diagnosis workup. Firstly, because clinical trials with MC4R-agonists have raised expectations regarding the treatment of patients with mutations of the LEPR gene. Secondly, and in contradiction to other reports in the literature, our patients were fertile. Therefore, identification of the mutation allows genetic counseling of these patients and their families, including the possibility of Pre-Natal Diagnosis or Pre-Implantation Genetic Diagnosis.

Association between leptin receptor gene polymorphism and quality of both meat and back fat in large white pigs of ukrainian breeding

2016 ◽  
Vol 3 (2) ◽  
pp. 42-48
Author(s):  
V. Balatsky ◽  
I. Bankovska ◽  
A. Saienko
Keyword(s):  
Gene Polymorphism ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Intramuscular Fat ◽  
Large White ◽  
Pig Breeds ◽  
Lepr Gene ◽  
Large White Breed ◽  
White Breed

Leptin receptor is one of the components of the system of regulating energy homeostasis of the organism. Leptin receptor gene (LEPR) polymorphism is associated with pig carcass index of the content of intramus- cular fat in its valuable parts, which is particularly important when assessing the quality of their carcasses for processing. Intramuscular fat is associated with meat fl avor characteristics and partly determines its tenderness, juiciness, and other parameters. Aim. To analyze LEPR gene (SNP NM001024587.1, p. 1987 C > T) polymor- phism in populations of various pig breeds and to establish its relationship with the quality of both meat and fat of pigs of Large White breed of Ukrainian breeding. Methods. Genetic-population analysis of nine pig breeds, associative analysis on the search connection of LEPR gene polymorphism with quality of both meat and fat of pigs of Large White breed of Ukrainian breeding. LEPR locus genotyping was performed by High Resolution Melting (HRM). Results. All the studied breeds are characterized by polymorphism of the leptin receptor gene (SNP NM001024587.1, p. 1987 C > T), signifi cant breed specifi city in the distribution of frequencies of alleles was established. Statistically confi rmed effect (p < 0.05) of genotypes LEPR on the content of intramuscular fat, total dry matter and moisture in the meat, as well as the moisture content in the back fat of pigs of Ukrainian Large White breed was revealed. Higher content of intramuscular fat was found in the animals with genotype TT, while a smaller amount of intramuscular fat and more moisture in fat was revealed in heterozygotes. Conclusions. Genetic marker LEPR SNP NM001024587.1, p. 1987 C > T can be used in the marker-assisted selection to predict and improve the performance quality of the meat of pigs of Large White breed of the Ukrainian breeding. These results suggest that porcine leptin receptor gene controls the quality of fat comp- lex – inside muscles and in the dorsal part of the carcass.

Relative leptin deficiency in children with severe early-onset obesity (SEOO) – results of the Early-onset Obesity and Leptin – German-Polish Study (EOL-GPS)

2020 ◽  
Vol 33 (2) ◽  
pp. 255-263 ◽  
Author(s):  
Agnieszka Zachurzok ◽  
Michael B. Ranke ◽  
Bertram Flehmig ◽  
Katarzyna Jakubek-Kipa ◽  
Katarzyna Marcinkiewicz ◽  
...  
Keyword(s):  
Early Onset ◽  
Leptin Receptor ◽  
Standard Deviation Score ◽  
Tanner Stage ◽  
Serum Levels ◽  
The Body ◽  
Biologically Active ◽  
World Health ◽  
Strong Negative Correlation ◽  
Leptin Deficiency

AbstractBackgroundSevere early-onset obesity (SEOO) in children is a common feature of monogenic obesity. Gene defects of the leptin-melanocortin pathway can be analysed biochemically and genetically. The aim of this study was to search for children with leptin deficiency or biologically inactive leptin in a cohort of children with SEOO and to study associations between leptin parameters and anthropometric data.MethodsThe cohort included n = 50 children with SEOO (22 boys) who were recruited at one of four study centres (Germany: Ulm; Poland: Katowice, Szczecin, Rzeszow) between October 2015 and October 2017. Weight (kg) and height (m) were measured, Tanner stage was obtained and a fasting serum blood sample was taken. Serum levels of total leptin (LEP, ng/mL), biologically active leptin (bioLEP, ng/mL) and soluble leptin receptor (sLEPR, ng/mL) were measured. The body mass index (BMI [kg/m2]), BMI z-score (World Health Organization [WHO]), quotient of bioLEP/LEP and leptin-standard deviation score (LEP-SDS) (Tanner stage, BMI and sex-adjusted) were calculated.ResultsWe did not find any child with leptin deficiency or biologically inactive leptin in our cohort. The serum LEP and bioLEP levels were strongly correlated with age (r = 0.50, p < 0.05) and BMI (r = 0.70; p < 0.0001). Girls had higher LEP and bioLEP levels (49.7 ± 35.9 vs. 37.1 ± 25.5 ng/mL, p > 0.05) as well as lower LEP-SDS than boys (−1.77 ± 2.61 vs. −1.40 ± 2.60, p > 0.05). sLEPR levels were negatively correlated with BMI values (r = −0.44; p < 0.05), LEP (r = −0.39; p < 0.05) and bioLEP levels (r = −0.37; p < 0.05). Interestingly, there was a strong inverse relationship between LEP-SDS and BMI (r = −0.72, p < 0.001).ConclusionsIn this cohort with SEOO, we identified no new cases of children with leptin deficiency or bioinactive leptin. A strong negative correlation between the LEP-SDS and BMI values could be interpreted as relative leptin deficiency in children with SEOO. In case this hypothesis can be confirmed, these children would benefit from a substitution therapy with methionyl human leptin (metreleptin™).

Linkage study of early-onset obesity to leptin receptor gene in Italian children

2000 ◽  
Vol 20 (8) ◽  
pp. 1059-1063 ◽  
Author(s):  
Emanuele Miraglia del Giudice ◽  
Laura Perrone ◽  
Paola Forabosco ◽  
Marcella Devoto ◽  
Maria Teresa Carbone ◽  
...  
Keyword(s):  
Early Onset ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Linkage Study ◽  
Italian Children

scholarly journals A critical view of the use of genetic tools to unveil neural circuits: the case of leptin action in reproduction

2014 ◽  
Vol 306 (1) ◽  
pp. R1-R9 ◽  
Author(s):  
Carol F. Elias
Keyword(s):  
Mouse Models ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Pubertal Development ◽  
Leptin Signaling ◽  
Genetic Tools ◽  
Virus Vectors ◽  
Neuronal Populations ◽  
Area Of Interest ◽  
Neuroendocrine Axis

The remarkable development and refinement of the Cre-loxP system coupled with the nonstop production of new mouse models and virus vectors have impelled the growth of various fields of investigation. In this article, I will discuss the data collected using these genetic tools in our area of interest, giving specific emphasis to the identification of the neuronal populations that relay leptin action in reproductive physiology. A series of mouse models that allow manipulation of the leptin receptor gene have been generated. Of those, I will discuss the use of two models of leptin receptor gene reexpression ( LepR neo/neo and LepR loxTB/loxTB) and one model of leptin signaling blockade ( LepR flox/flox). I will also highlight the differences of using stereotaxic delivery of virus vectors expressing DNA-recombinases (Flp and Cre) and mouse models expressing Cre-recombinase. Our findings indicate that leptin action in the ventral premammillary nucleus is sufficient, but not required, for leptin action in reproduction and that leptin action in Kiss1 neurons arises after pubertal maturation; therefore, direct leptin signaling in Kiss1 neurons is neither required nor sufficient for the permissive action of leptin in pubertal development. It also became evident that the full action of leptin in the reproductive neuroendocrine axis requires the engagement of an integrated circuitry, yet to be fully unveiled.

scholarly journals The transcript expression profile of the leptin receptor-coding gene assayed with the oligonucleotide microarray technique — Could this be an Anorexia nervosa marker?

2006 ◽  
Vol 11 (1) ◽  
Author(s):  
Małgorzata Janas-Kozik ◽  
Urszula Mazurek ◽  
Irena Krupka-Matuszczyk ◽  
Małgorzata Stachowicz ◽  
Joanna Głogowska-Ligus ◽  
...  
Keyword(s):  
Anorexia Nervosa ◽  
Expression Profile ◽  
Leptin Receptor ◽  
Reference Group ◽  
Receptor Gene ◽  
Oligonucleotide Microarray ◽  
The Body ◽  
Transcript Expression ◽  
Mrna Isoforms ◽  
Psychic Disorders

AbstractAnorexia nervosa is a serious eating disorder with the highest mortality rate of any psychiatric disorder. The DSM-IV classification differentiates two AN types: the restricting type (AN-R) and the binge-eating/purging type (AN-BP). Leptin (LEP) levels can be thought of as a signal to the body of its energy reserves. The leptin receptor (including all its mRNA isoforms) is expressed in many tissues. Our aim was to discover the transcript expression profile of the LEP receptor-coding gene in the peripheral blood mononuclears in AN-R and AN-BP patients. Three young women suffering from Anorexia nervosa (one with AN-BP and two with AN-R) took part in the study, along with three non-anorexic subjects as our reference group. LEP receptor gene expression was examined using the oligonucleotide microarray method (HG-U133A, Affymetrix). The results were normalized using RMAExpress. Next, the accumulation analysis method was used (clustering). Hierarchical clustering resulted in three groups of separate clusters. The first group (cluster I) consisted of AN-R patients. The next group (cluster II) consisted of reference group patients suffering from different psychic disorders not related to eating disorders. Cluster III consisted of two patients — the first with AN-BP and the second with an adaptive disorder.

Neonatal Schwartz-Jampel syndrome type II: a rare case of peripheral origin of neonatal hypertonia

2021 ◽  
Vol 14 (7) ◽  
pp. e240397
Author(s):  
Arjun Verma ◽  
Nishant Banait ◽  
Pradeep Suryawanshi ◽  
Reema Garegrat
Keyword(s):  
Genetic Disorder ◽  
Receptor Gene ◽  
Genetic Diagnosis ◽  
Severe Form ◽  
Leukaemia Inhibitory Factor ◽  
Homozygous Mutation ◽  
Syndrome Type ◽  
Type Ii ◽  
Feeding Difficulties ◽  
Peripheral Origin

Neonatal Schwartz-Jampel syndrome type II is a rare and severe form of genetic disorder. Different from the classical appearance in infancy, neonatal presentation involves respiratory and feeding difficulties, along with characteristic pursed appearance of the mouth, myotonia, skeletal dysplasia and severe fatal hyperthermia. The clinical spectrum of this syndrome is so wide that it easily baffles with more common differentials. In this case report, a neonate born to third-degree consanguineous marriage with previous two abortions presented with respiratory difficulty, severe hyperthermia and feeding difficulty, which were daunting challenges to manage due to being refractory to standard line of management. Severe myotonia and gross dysmorphism were challenging dots to connect. Targeted exome sequencing was a ray of hope, which revealed homozygous mutation in the leukaemia inhibitory factor receptor gene on chromosome 5p13, confirming the genetic diagnosis for a fairly common spectrum of symptoms. The neonate later developed pneumoperitoneum and succumbed to underlying severe neonatal illness.

Association between leptin receptor gene polymorphisms and early-onset prostate cancer

2003 ◽  
Vol 92 (1) ◽  
pp. 109-112 ◽  
Author(s):  
Z. Kote-Jarai ◽  
R. Singh ◽  
F. Durocher ◽  
D. Easton ◽  
S.M. Edwards ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Early Onset ◽  
Gene Polymorphisms ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Receptor Gene Polymorphisms

scholarly journals Association of leptin receptor gene polymorphisms and meta-inflammation markers with metabolically unhealthy obesity in children

2021 ◽  
Vol 23 (5) ◽  
pp. 696-702
Author(s):  
А. Е. Abaturov ◽  
A. O. Nikulina
Keyword(s):  
Leptin Receptor ◽  
Receptor Gene ◽  
Strong Association ◽  
Main Group ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Inflammation Markers ◽  
Obese Children ◽  
Lepr Gene ◽  
Metabolically Unhealthy Obesity

The aim: to study the contribution of single-nucleotide polymorphisms (SNP) of the leptin receptor (LEPR) gene and meta-inflammation markers to the formation of metabolically unhealthy obesity (MUO) in children. Materials and methods. A total of 109 obese children aged 6–18 years were examined. Based on the recommendations of the National Heart, Lung, and Blood Institute (NHLBI), 2 observation groups were formed. The main group (n = 56) was represented by patients with MUO. The control group (n = 53) comprised children with metabolically healthy obesity (MHO). Serum levels of interleukin-1β (IL-1β) were measured using a chemiluminescent immunoassay (CLIA) method, interleukin-6, leptin, adiponectin – by enzyme-linked immunosorbent assay (ELISA) and the serum level of C-reactive protein were quantified by latex turbidimetric method (Synevo, Ukraine). The method of next-generation sequencing (NGS) (CeXGat, Germany) was used to identify LEPR SNP. Statistical methods were used: analysis of variance, Spearman’s correlation analysis and multiple discriminant analysis. Results. In obese children aged 6 to 18 years, there was an increase in pro-inflammatory adipokines IL-6 and leptin and a decrease in anti-inflammatory adiponectin. Statistically significant changes in these indicators were more expressed in the main group: IL-6 – 7.4 ± 0.5 pg/ml (ρ = 0.65; P ≤ 0.001); adiponectin – 3.9 ± 0.8 μg/ml (ρ = -0.27; P = 0.007) among all the children examined, leptin in girls – 47.8 ± 4.4 ng/ml (ρ = -0.28; P = 0.003) compared with the results of patients in the control group: IL-6 – 4.3 ± 0.3 pg/ml, adiponectin – 7.7 ± 2.4 μg/ml, leptin in girls – 32.5 ± 4.3 ng/ml, P ≤ 0.05. The most important in the development of MUO were the following SNP of the LEPR gene: rs3790435 (CiMUO = 0.939), rs2186248 (CiMUO = 0.862), P < 0.05. A strong correlation was found between MUO and serum IL-6 level (ρ = 0.7), LEPR SNP rs3790435 (ρ = 0.7), basal hyperinsulinemia (ρ = 0.72); Р ≤ 0.001. The risk of IL-6-dependent meta-inflammation in the presence of SNP rs3790435 of the LEPR gene: OR = 17.11; 95 % CI 2.8–20.4. Conclusions. Meta-inflammation in MUO is IL-6-dependent. Among the 10 SNPs of the LEPR gene that we identified, SNP rs3790435 of the LEPR gene has a strong association with the formation of MUO. SNP rs2186248 LEPR was described by us for the first time when it was found in 94.1 % of obese children, but it was characterized by the presence of a weak association with MUO.

scholarly journals Phenotypic variation in constitutional delay of growth and puberty: relationship to specific leptin and leptin receptor gene polymorphisms

2006 ◽  
Vol 155 (1) ◽  
pp. 121-126 ◽  
Author(s):  
Indraneel Banerjee ◽  
Julie A Trueman ◽  
Catherine M Hall ◽  
David A Price ◽  
Leena Patel ◽  
...  
Keyword(s):  
Gene Polymorphisms ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Pubertal Development ◽  
Bone Age ◽  
Short Allele ◽  
Pubertal Delay ◽  
The Us ◽  
Constitutional Delay ◽  
Bone Age Delay

Objectives: Constitutional delay of growth and puberty (CDGP) is a variant of normal pubertal timing and progress, often with dominant inheritance. It is likely that one or more genes will be associated with CDGP. Possible candidates are the leptin (L) and the leptin receptor (LR) genes, as the leptin axis links nutritional status to pubertal development. This study has assessed whether a) L or LR gene polymorphisms were associated with CDGP and b) the CDGP phenotype was influenced by these polymorphisms. Design: Case–control and transmission disequilibrium tests were used to test genetic association of L and LR polymorphisms with CDGP. Methods: We genotyped L (3′CTTT repeat) and LR polymorphisms (Gln>Arg substitution, exon 6) in 81 CDGP children and 94 controls in the UK and 88 CDGP children from the US and assessed the effect of genotype on their anthropometric characteristics. Results: There was no association of these L or LR gene polymorphisms with CDGP. There was no difference in height or bone age delay within L or LR genotypes. However, UK CDGP children homozygous for the L short allele were heavier than heterozygotes and long allele homozygotes, with a similar trend in the US cohort. UK CDGP children with severe pubertal delay, who were thin, had significantly greater bone age delay and an increased frequency of parental pubertal delay than other groups and were less likely to be L short allele homozygotes. Conclusions: There was no association of specific L or LR polymorphisms with CDGP, but L short allele carriage influenced the phenotype within CDGP.

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