The Spectrum of Genetic Variants Associated with the Development of Monogenic Obesity in Qatar

AbouHashem, Nadien; Zaied, Roan E.; Al-Shafai, Kholoud; Nofal, Mariam Y.; Syed, Najeeb; Al-Shafai, Mashael

doi:10.1159/000521851

Cited by 14 publications

(7 citation statements)

References 48 publications

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“…Indeed, in a study by Kleinendorst et al, two Dutch individuals received a definitive diagnosis for genetic obesity, solely attributed to the heterozygous PCSK1 p.Y181H variant [ 36 ]. In a recent study by AbouHashem et al [ 42 ], a heterozygous PCSK1 nonsynonymous variant carrier was also diagnosed with monogenic obesity. As genetic diagnosis of patients can have a profound impact on tailored treatment options and care, we urge that at present, all rare heterozygous PCSK1 variants should be carefully and individually assessed before genetic obesity diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review

Dijck

Beckers

Diels

et al. 2022

Genes

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Recently, it was reported that heterozygous PCSK1 variants, causing partial PC1/3 deficiency, result in a significant increased risk for obesity. This effect was almost exclusively generated by the rare p.Y181H (rs145592525, GRCh38.p13 NM_000439.5:c.541T>C) variant, which affects PC1/3 maturation but not enzymatic capacity. As most of the identified individuals with the heterozygous p.Y181H variant were of Belgian origin, we performed a follow-up study in a population of 481 children and adolescents with obesity, and 486 lean individuals. We identified three obese (0.62%) and four lean (0.82%) p.Y181H carriers (p = 0.506) through sanger sequencing and high resulting melting curve analysis, indicating no association with obesity. Haplotype analysis was performed in 13 p.Y181H carriers, 20 non-carriers (10 with obesity and 10 lean), and two p.Y181H families, and showed identical haplotypes for all heterozygous carriers (p < 0.001). Likewise, state-of-the-art literature concerning the role of rare heterozygous PCSK1 variants implies them to be rarely associated with monogenic obesity, as first-degree carrier relatives of patients with PC1/3 deficiency are mostly not reported to be obese. Furthermore, recent meta-analyses have only indicated a robust association for scarce disruptive heterozygous PCSK1 variants with obesity, while clinical significance is less or sometimes lacking for most nonsynonymous variants.

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Section: Discussionmentioning

confidence: 99%

Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review

Dijck

Beckers

Diels

et al. 2022

Genes

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“…Nowadays, mutations in at least 50 genes are known to be related to monogenic obesity, and many others are tested ( 1 , 8 , 17 – 19 ). Many of them are involved in the leptin–proopiomelanocortin pathway.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is a group of patients in whom a monogenic cause of obesity can be identified. This group is usually characterized by severe obesity with early onset, before the age of 6 years (severe early-onset obesity (SEOO)) ( 1 ). Kohlsdorf et al.…”

Section: Introductionmentioning

confidence: 99%

Clinical, genetic, and epidemiological survey of Polish children and adolescents with severe obesity: A study protocol of the Polish–German study project on severe early-onset obesity

et al. 2022

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Severe early-onset obesity (SEOO) in children is a common feature of monogenic obesity. Nowadays, mutations in at least 50 genes are known to be related to monogenic obesity, and many others are tested. Part of them is involved in the leptin–proopiomelanocortin pathway. The aim of the project is to establish the Polish database of severely obese children and adolescents and to evaluate the prevalence of monogenic forms of obesity in this cohort, with a special focus on leptin–proopiomelanocortin pathway abnormalities. The secondary project aim is to identify new population-specific mutations in obesity-related genes in severely obese Polish children and adolescents. This is a prospective multi-center clinical study performed in four Polish centers. The estimated sample size is 500 patients aged 1–18 years, with severe obesity, hyperphagia, and food-seeking behaviors. In each patient, the medical history regarding the obesity duration in the patient and obesity and its complication existence in the family will be taken. Next, the questionnaire regarding the symptom characteristic of specific mutations, which we are going to test, will be performed. Hyperphagia will be assessed on the basis of age-specific questionnaires. The physical examination with anthropometric measurement, basic biochemical and hormonal tests, and leptin and biologically active leptin measurements will be performed. Finally, genetic analysis will be performed using next-generation sequencing with sequencing libraries prepared to include obesity-related genes. The genotyping findings will be confirmed with the use of classic sequencing (Sanger’s method). In the future, the pathogenicity of new mutations in obesity-related genes identified in our cohort is planned to be confirmed by functional testing in vitro. Nowadays, there are no data regarding the prevalence of severe obesity or monogenic obesity in Polish children. This project has the potential to improve understanding of obesity etiology and may contribute to implementing attribute mutation-specific treatment. Moreover, it may lead to a finding of new, population-specific mutations related to SEOO.

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“…Nevertheless, genetic factors have been shown to play an important role in the development of both diseases. 5,6 Adenylate cyclase 3 (Adcy3) has been established as an important gene for both obesity and MDD, supported by both human [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] and rodent [22][23][24][25][26][27][28] studies. 29 ADCY3 is a plasma membraneassociated protein that catalyzes the synthesis of cAMP, a secondary messenger that has itself been linked to the development and treatment of obesity and MDD.…”

Section: Introductionmentioning

confidence: 99%

Protein-coding mutation inAdcy3increases adiposity and alters emotional behaviors sex-dependently in rats

Fitzpatrick,

Szalanczy,

Beeson

et al. 2024

Preprint

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1AbstractObjectiveAdenylate cyclase 3 (Adcy3)has been linked to both obesity and major depressive disorder (MDD). Our lab identified a protein-coding variant in the 2ndtransmembrane (TM) helix ofAdcy3in rats, and similar obesity variants have been identified in humans. The current study investigates the role of a TM variant in adiposity and behavior.MethodsWe used CRISPR-SpCas9 to mutate the TM domain ofAdcy3in WKY rats (Adcy3mut/mut). We also created a heterozygous knockout rat in the same strain (Adcy3+/-). Wild-type (WT), Adcy3+/-, and Adcy3mut/mutrats were fed a high-fat diet for 12 weeks. We measured body weight, fat mass, glucose tolerance, food intake, metabolism, emotion-like behaviors, and memory.ResultsAdcy3+/-and Adcy3mut/mutrats weighed more than WT rats due to increased fat mass. There were key sex differences: adiposity was driven by increased food intake in males but by decreased energy expenditure in females. Adcy3mut/mutmales displayed increased passive coping and decreased memory while Adcy3mut/mutfemales displayed increased anxiety-like behavior.ConclusionsThese studies show that the ADCY3 TM domain plays a role in protein function, thatAdcy3may contribute to the relationship between obesity and MDD, and that sex influences the relationships betweenAdcy3, metabolism, and behavior.Study Importance QuestionsWhat is already known about this subject?Adcy3has been linked to both obesity and depression in humans, with protein-coding variants in the transmembrane domain leading to increased obesity. Yet the underlying mechanisms are unknown, and it is unknown if the sameAdcy3variants can cause both obesity and depression.RodentAdcy3knockout models show increased adiposity and altered emotional behaviors, but no rodent models have assessed the role of protein-coding variants inAdcy3.Very few studies have assessed sex differences.What are the new findings in your manuscript?This is the first study to assess the role of a protein-coding variant in the transmembrane domain ofAdcy3, showing increases in both obesity and emotion-like behaviors in a rat model.We observed striking sex differences, where male and female rats had different factors driving their adiposity and different patterns of altered behavior.How might your results change the direction of research or the focus of clinical practice?Understanding the role ofAdcy3in obesity and MDD may lead to improved treatments for both diseases.Improving our understanding of the sex differences caused by the sameAdcy3mutation emphasizes the importance of studying both sexes and paves the way for personalized medicine approaches.

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The Spectrum of Genetic Variants Associated with the Development of Monogenic Obesity in Qatar

Cited by 14 publications

References 48 publications

Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review

Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review

Clinical, genetic, and epidemiological survey of Polish children and adolescents with severe obesity: A study protocol of the Polish–German study project on severe early-onset obesity

Protein-coding mutation inAdcy3increases adiposity and alters emotional behaviors sex-dependently in rats

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