scholarly journals Monogenic Obesity

2020 ◽  
Author(s):  
Keyword(s):  
Monogenic Obesity

scholarly journals Obesity in Childhood and Adolescence, Genetic Factors

PRILOZI ◽  
2017 ◽  
Vol 38 (3) ◽  
pp. 121-133 ◽  
Author(s):  
Marko Kostovski ◽  
Velibor Tasic ◽  
Nevena Laban ◽  
Momir Polenakovic ◽  
Dragan Danilovski ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Rapid Onset ◽  
Modern World ◽  
Childhood And Adolescence ◽  
Monogenic Obesity ◽  
Wagr Syndrome ◽  
The Family ◽  
Genetic Mechanisms ◽  
Childhood And Adolescent Obesity ◽  
Carbohydrate Intolerance

AbstractObesity and excess weight are a pandemic phenomenon in the modern world. Childhood and adolescent obesity often ends up in obesity in adults. The costs of obesity and its consequences are staggering for any society, crippling for countries in development. Childhood obesity is also widespread in Macedonia. Metabolic syndrome, dyslipidemia and carbohydrate intolerance are found in significant numbers. Parents and grandparents are often obese. Some of the children are either dysmorphic, or slightly retarded. We have already described patients with Prader-Willi syndrome, Bardet-Biedl syndrome or WAGR syndrome. A genetic screening for mutations in monogenic obesity in children with early, rapid-onset or severe obesity, severe hyperphagia, hypogonadism, intestinal dysfunction, hypopigmentation of hair and skin, postprandial hypoglycaemia, diabetes insipidus, abnormal leptin level and coexistence of lean and obese siblings in the family discovers many genetic forms of obesity. There are about 30 monogenic forms of obesity. In addition, obesity is different in ethnic groups, and the types of monogenic obesity differ. In brief, an increasing number of genes and genetic mechanisms in children continue to be discovered. This sheds new light on the molecular mechanisms of obesity and potentially gives a target for new forms of treatment.

scholarly journals OR33-07 ARNT2: A Potential Novel Candidate Gene for Monogenic Obesity in Humans

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Vidhu V Thaker ◽  
Eleanor G Seaby ◽  
Casie Genetti ◽  
Jacob Sutherland ◽  
Grazia Ianello ◽  
...  
Keyword(s):  
Early Onset ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Focal Epilepsy ◽  
Critical Role ◽  
Hek293 Cells ◽  
Luciferase Reporter ◽  
Patient Specific ◽  
Monogenic Obesity ◽  
Caucasian Girl

Abstract Introduction: Aryl hydrocarbon nuclear translocator 2 (ARNT2) is a basic helix-loop-helix (bHLH)-PAS (Per/Arnt/Sim) transcription factor shown to be critical to the development of paraventricular nucleus of the hypothalamus (PVN), key region for energy homeostasis and feeding response. In vivo and in vitro studies have shown that ARNT2 is an obligate heterodimer for SIM1, known cause of monogenic obesity. Null mutations in Arnt2 in animals are not viable, but hypomorphic mutation results in hyperphagic obesity and its associated consequences (1). Due to the critical role of ARNT2 in the development of PVN, we hypothesize that hypomorphic mutations may result in early onset obesity in humans. Methods: The Genetics of Early Childhood Obesity (GECO) study recruits children with severe obesity (BMI > 120% of 95th percentile) of early onset (< 6 years). Whole exome sequencing (WES) was performed in a subset of proband-parent trios. The functional validation of the mutation(s) in ARNT2 is ongoing with co-transfection of tagged Arnt2 and Sim1 in HEK293 cells, with the induction of a luciferase reporter gene under the control of 6 repeats of bHLH-PAS core binding element by the Arnt2-Sim1 complex. Results: Two adolescents from unrelated families were found to have genetic variants in ARNT2. Subject 1 has a novel de novo heterozygous coding variant in ARNT2, c.388 C>G (p.P130A, CADD 25), predicted to be deleterious by 8/12 in silico algorithms. She is a 14-year old Caucasian girl with severe early onset obesity, BMI 28.1 kg/m2 (BMIz +4.72) at 2.5 years of age that has increased to 53.54 kg/m2 (BMIz + 3.25) at 14-years, and height > 95th %tile. She is non-dysmorphic, has developmental delay, absence seizures, behavior abnormalities & glucose intolerance/dyslipidemia secondary to obesity. Using genematcher, we identified another proband with the phenotype of obesity: an African American girl (BMIz +1.9) with biallelic inherited heterozygous variants in ARNT2, c.1228T>A (p.W410R, CADD 29) and c.916G>A (p.G306S, CADD 22). An only child conceived by IVF, she is non-dysmorphic and on treatment for bilateral focal epilepsy. All 3 variants are rare, with mean allele frequency < 0.005 in population-based databases such as gNOMAD. Both the patients have early onset obesity and a significant neurological phenotype. ARNT2 is a highly constrained gene of 717 amino acids with a significant depletion of missense variants in the N-terminus (1-244 aa) and overall fewer loss of function variants in ~282,644 alleles sequenced in gNOMAD. Conclusions: We propose that hypomorphic mutations in ARNT2 could be a potential novel cause of monogenic obesity in humans. Future studies will investigate the molecular mechanisms causing weight dysregulation in patient specific disease relevant hypothalamic neurons. Reference: (1) Turer et al., Dis Model Mech. 2018; 11(12)

Monogenic Obesity

2017 ◽  
pp. 135-152 ◽  
Author(s):  
Marie Pigeyre ◽  
David Meyre
Keyword(s):  
Monogenic Obesity

Pseudohypoparathyroidism - another monogenic obesity syndrome

2000 ◽  
Vol 52 (3) ◽  
pp. 389-391 ◽  
Author(s):  
Ken K. L. Ong ◽  
Rakesh Amin ◽  
David B. Dunger
Keyword(s):  
Monogenic Obesity ◽  
Obesity Syndrome

scholarly journals A Novel Mutation inLeptinGene Is Associated with Severe Obesity in Chinese Individuals

2014 ◽  
Vol 2014 ◽  
pp. 1-3 ◽  
Author(s):  
Yue Zhao ◽  
Nanchao Hong ◽  
Xiao Liu ◽  
Beibei Wu ◽  
Shanshan Tang ◽  
...  
Keyword(s):  
Severe Obesity ◽  
Novel Mutation ◽  
Single Gene ◽  
Clinical Syndrome ◽  
Nonsynonymous Mutation ◽  
Rare Type ◽  
Monogenic Obesity ◽  
Genetic And Environmental Factors ◽  
Clinical Measurements ◽  
Chinese Subjects

Obesity is a clinical syndrome which is driven by interactions between multiple genetic and environmental factors. Monogenic obesity is a rare type of obesity which is caused by a mutation in a single gene. Patients with monogenic obesity may develop early onset of obesity and severe metabolic abnormalities. In this study, we screened mutations ofLEPin a total of 135 Chinese individuals including 35 obese patients whose BMI ≥32 kg/m2and 100 controls with BMI <25 kg/m2. Moreover, detailed information and clinical measurements of the participants were also collected. Finally, we identified a novel nonsynonymous mutation H118L in exon 3 ofLEPin one patient with BMI 46.0 kg/m2. This mutation was not identified in the controls. We speculated that the mutation H118L inLEPmight be associated with severe obesity in Chinese subjects. However, the substantial mechanism should be further investigated.

Early childhood BMI trajectories in monogenic obesity due to leptin, leptin receptor, and melanocortin 4 receptor deficiency

2018 ◽  
Vol 42 (9) ◽  
pp. 1602-1609 ◽  
Author(s):  
Katja Kohlsdorf ◽  
Adriana Nunziata ◽  
Jan-Bernd Funcke ◽  
Stephanie Brandt ◽  
Julia von Schnurbein ◽  
...  
Keyword(s):  
Early Childhood ◽  
Leptin Receptor ◽  
Monogenic Obesity ◽  
Melanocortin 4 Receptor ◽  
Bmi Trajectories
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