Rare Variants in Genes Linked to Appetite Control and Hypothalamic Development in Early-Onset Severe Obesity

Loid, Petra; Mustila, Taina; Mäkitie, Riikka E.; Viljakainen, Heli; Kämpe, Anders; Tossavainen, Päivi; Lipsanen‐Nyman, Marita; Pekkinen, Minna; Mäkitie, Outi

doi:10.3389/fendo.2020.00081

Cited by 25 publications

(26 citation statements)

References 42 publications

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“…ADCY3 variants in association with obesity were identified in various human population studies. All reported data are presented in Table III (15,16,(31)(32)(33)(34). More specifically, ADCY3 variants (rs2033655 and rs1968482) were reported to be associated with obesity in a population of Swedish males with or without type 2 diabetes in 2008 (16).…”

Section: Discussionmentioning

confidence: 99%

Molecular modelling of novel ADCY3 variant predicts a molecular target for tackling obesity

Toumba¹,

Fanis

Vlachakis

et al. 2021

Int J Mol Med

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Severe early-onset obesity is mainly attributed to single gene variations of the hypothalamic leptin-melanocortin system, which is critical for controlling the balance between appetite and energy expenditure. Adenylate cyclase 3 (ADCY3), a transmembrane enzyme localized in primary neuronal cilia, is a key genetic candidate, which appears to have an essential role in regulating body weight. The present study aimed to identify ADCY3 genetic variants in severely obese young patients of Greek-Cypriot origin by genomic sequencing. Apart from previously reported variants, the novel and probably pathogenic variant c.349T>A, causing a p.Leu117Met substitution within one of the two pseudo-symmetric halves of the transmembrane part of the protein, was reported. Molecular modelling analysis used to delineate bonding interactions within the mutated protein structure strongly suggested a change in interactive forces and energy levels affecting the pseudo-twofold symmetry of the transmembrane domain of the protein and probably its catalytic function. These results support the involvement of ADCY3 in the pathology of the disease and point towards the requirement of defining protein function and evaluating the clinical significance of the detected variants.

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Section: Discussionmentioning

confidence: 99%

Molecular modelling of novel ADCY3 variant predicts a molecular target for tackling obesity

Toumba¹,

Fanis

Vlachakis

et al. 2021

Int J Mol Med

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show abstract

“…More common are mutations in the MC4R gene, which have been shown to cause both dominant and recessive forms of monogenic obesity [ 50 , 51 , 52 , 53 ] and are responsible for up to 6% of severe, early-onset obesity cases [ 46 , 54 , 55 , 56 ]. More recently, MC4R variants with less severe effects on receptor function have been shown to be major modifiers of obesity risk in the wider human population [ 57 , 58 , 59 ].…”

Section: Studies Of Monogenic Obesity Have Been Highly Informativementioning

confidence: 99%

“…Although cases of monogenic obesity exist, they account for only 5–7% of severe obesity cases [ 17 , 54 , 64 ] and much less of the obesity that develops later in life. Common obesity is a complex trait, caused by the additive effect of hundreds, possibly even thousands, of common genetic variants [ 65 ].…”

Section: Common Human Obesitymentioning

confidence: 99%

The Genetic Basis of Obesity and Related Metabolic Diseases in Humans and Companion Animals

Wallis

Raffan

2020

Genes

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Obesity is one of the most prevalent health conditions in humans and companion animals globally. It is associated with premature mortality, metabolic dysfunction, and multiple health conditions across species. Obesity is, therefore, of importance in the fields of medicine and veterinary medicine. The regulation of adiposity is a homeostatic process vulnerable to disruption by a multitude of genetic and environmental factors. It is well established that the heritability of obesity is high in humans and laboratory animals, with ample evidence that the same is true in companion animals. In this review, we provide an overview of how genes link to obesity in humans, drawing on a wealth of information from laboratory animal models, and summarise the mechanisms by which obesity causes related disease. Throughout, we focus on how large-scale human studies and niche investigations of rare mutations in severely affected patients have improved our understanding of obesity biology and can inform our ability to interpret results of animal studies. For dogs, cats, and horses, we compare the similarities in obesity pathophysiology to humans and review the genetic studies that have been previously reported in those species. Finally, we discuss how veterinary genetics may learn from humans about studying precise, nuanced phenotypes and implementing large-scale studies, but also how veterinary studies may be able to look past clinical findings to mechanistic ones and demonstrate translational benefits to human research.

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“…More common are mutations in the MC4R gene, which have been shown to cause both dominant and recessive forms of monogenic obesity [45][46][47][48] and which are responsible for up to 6% of severe, earlyonset obesity cases [41,[49][50][51]. More recently, MC4R variants with less severe effects on receptor function have been shown to be major modifiers of obesity risk in the wider human population [52].…”

Section: Disruption Of Leptin-melanocortin Signalling Leads To Obesitymentioning

confidence: 99%

“…Although cases of monogenic obesity exist, they account for only 5-7% of severe obesity cases [14,49,57]. Common obesity is a complex trait, caused by the additive effect of hundreds, possibly even thousands, of common genetic variants [58].…”

Section: Common Human Obesitymentioning

confidence: 99%

The Genetic Basis of Obesity and Related Metabolic Diseases in Humans and Companion Animals

Wallis

Raffan

2020

Preprint

View full text Add to dashboard Cite

Obesity is one of the most prevalent health conditions in humans and companion animals across the world. Obesity is associated with multiple health conditions across species including premature mortality. It is therefore of importance across the fields of medicine and veterinary medicine. The regulation of body weight is a homeostatic process vulnerable to disruption by genetic and environmental factors. It is well established that the heritability of obesity is high in humans and laboratory animals, with ample evidence that the same is true in companion animals. In this review, we provide an overview of how genes link to obesity in humans, drawing on a wealth of information from laboratory animal models, and summarising the mechanisms by which obesity causes related disease. Throughout, we focus on how large-scale human studies and niche investigations of rare mutations in severely affected patients have improved our understanding of obesity biology and can inform our ability to interpret results of animal studies. For dogs, cats and horses, we review the similarities in obesity pathophysiology to humans and review those genetic studies that have been done to investigate them. Finally, we discuss how veterinary genetics may learn from humans about studying precise, nuanced phenotypes and implementing large-scale studies, but also how veterinary studies may be able to look past clinical findings to mechanistic ones and demonstrate translational benefits to human research.

show abstract

Rare Variants in Genes Linked to Appetite Control and Hypothalamic Development in Early-Onset Severe Obesity

Cited by 25 publications

References 42 publications

Molecular modelling of novel ADCY3 variant predicts a molecular target for tackling obesity

Molecular modelling of novel ADCY3 variant predicts a molecular target for tackling obesity

The Genetic Basis of Obesity and Related Metabolic Diseases in Humans and Companion Animals

The Genetic Basis of Obesity and Related Metabolic Diseases in Humans and Companion Animals

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