Characterization of Rare Variants in MC4R in African American and Latino Children With Severe Early-Onset Obesity

Rosa, Maria Caterina De; Chesi, Alessandra; McCormack, Shana E.; Zhou, Jun; Weaver, Benjamin; McDonald, Molly; Christensen, Sinead; Liimatta, Kalle; Rosenbaum, Michael; Hákonarson, Hákon; Doege, Claudia A.; Grant, Struan F.A.; Hirschhorn, Joel N.; Thaker, Vidhu

doi:10.1210/jc.2018-02657

Cited by 21 publications

(23 citation statements)

References 32 publications

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“…The prevalence of pathogenic variants in MC4R in our cohort was 2% (2/92), which is comparable to previous reports (7,(10)(11)(12)(13)(14). The patients in our study with the novel MC4R frameshift deletion had severe childhood obesity and hyperphagia.…”

Section: Discussionsupporting

confidence: 86%

“…Of them, MC4R mutations are the most frequent with over 300 reported variants (9). The prevalence of pathogenic variants in MC4R in Finnish patients with early-onset obesity was reported to be 1.8% (10), and in other populations 1.5-5.8% (7,(11)(12)(13)(14). Patients with loss-of-function MC4R mutations typically present with severe childhood obesity, hyperphagia, hyperinsulinemia, and increased linear growth (11,15).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Context: The hypothalamic circuit has an essential role in the regulation of appetite and energy expenditure. Pathogenic variants in genes involved in the hypothalamic leptin-melanocortin pathway, including melanocortin-4-receptor (MC4R), have been associated with monogenic obesity.Objective: To determine the rate and spectrum of rare variants in genes involved in melanocortin pathway or hypothalamic development in patients with severe early-onset obesity (height-adjusted weight >60% before age 10 years). Methods:We used a custom-made targeted exome sequencing panel to assess peripheral blood DNA samples for rare (minor allele frequency <0.5%), pathogenic/likely pathogenic variants in 24 genes related to the hypothalamic circuit in 92 subjects (51% males, median age 13.7 years) with early-onset severe obesity (median body mass index (BMI) Z-score + 4.0).

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…One example is F202L, a variant that is more prevalent in people of African ancestry (MAF, 0.9%) ( Logan et al., 2015 ) and was found in 6 unrelated people of African ancestry in the Genetics of Obesity Study (GOOS) cohort (n = 7,447 screened). Our findings establish a role for this variant in weight gain in people of African ancestry ( De Rosa et al., 2019 ; Logan et al., 2015 ) with implications for carriers who may benefit from treatments that are effective in MC4R deficiency. People with heterozygous MC4R deficiency can respond to treatment with the GLP-1 receptor agonist liraglutide ( Iepsen et al., 2018 ) and with Roux-en-Y-bypass surgery ( Hatoum et al., 2012 ), but those with homozygous MC4R mutations may not respond to bypass surgery, although they may to GLP1 receptor agonism ( Iepsen et al., 2020 ).…”

Section: Discussionsupporting

confidence: 54%

Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation

et al. 2021

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Summary The Melanocortin-4 Receptor (MC4R) plays a pivotal role in energy homeostasis. We used human MC4R mutations associated with an increased or decreased risk of obesity to dissect mechanisms that regulate MC4R function. Most obesity-associated mutations impair trafficking to the plasma membrane (PM), whereas obesity-protecting mutations either accelerate recycling to the PM or decrease internalization, resulting in enhanced signaling. MC4R mutations that do not affect canonical Gα s protein-mediated signaling, previously considered to be non-pathogenic, nonetheless disrupt agonist-induced internalization, β-arrestin recruitment, and/or coupling to Gα s , establishing their causal role in severe obesity. Structural mapping reveals ligand-accessible sites by which MC4R couples to effectors and residues involved in the homodimerization of MC4R, which is disrupted by multiple obesity-associated mutations. Human genetic studies reveal that endocytosis, intracellular trafficking, and homodimerization regulate MC4R function to a level that is physiologically relevant, supporting the development of chaperones, agonists, and allosteric modulators of MC4R for weight loss therapy.

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“…This number is comparable to previous findings in another Dutch tertiary pediatric cohort (2.1%) [40] and 1.6-2.6% in other non-consanguineous pediatric cohorts screening for genetic obesity. [41,42] However, in many studies, only MC4R mutations or a small number of obesity-associated genes are tested. [7,27,[40][41][42][43] In our cohort, 13 genetic obesity disorders other than MC4R were present.…”

Section: Plos Onementioning

confidence: 99%

Identifying underlying medical causes of pediatric obesity: Results of a systematic diagnostic approach in a pediatric obesity center

et al. 2020

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Background Underlying medical causes of obesity (endocrine disorders, genetic obesity disorders, cerebral or medication-induced obesities) are thought to be rare. Even in specialized pediatric endocrinology clinics, low diagnostic yield is reported, but evidence is limited. Identifying these causes is vital for patient-tailored treatment. Objectives To present the results of a systematic diagnostic workup in children and adolescents referred to a specialized pediatric obesity center. Methods This is a prospective observational study. Prevalence of underlying medical causes was determined after a multidisciplinary, systematic diagnostic workup including growth charts analysis, extensive biochemical and hormonal assessment and genetic testing in all patients.

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Characterization of Rare Variants in MC4R in African American and Latino Children With Severe Early-Onset Obesity

Cited by 21 publications

References 32 publications

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

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

Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation

Identifying underlying medical causes of pediatric obesity: Results of a systematic diagnostic approach in a pediatric obesity center

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