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Functional alterations of two novel MC4R mutations found in Argentinian pediatric patients with early onset obesity
Estefanía Fernández1, Clara Inés McCarthy2, Ramiro Hector Cerviño3
1Laboratorio de Genética Molecular, Instituto Multidisciplinario de Biología Celular (IMBICE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de La Plata (UNLP) y Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CIC-PBA), La Plata, Buenos Aires, Argentina.
Insights
Loss-of-function mutations in the melanocortin-4 receptor (MC4R) cause early-onset obesity. Researchers identified two new MC4R mutations in Argentinian children, revealing a 2.1% prevalence and providing insights into disease mechanisms.
Area of Science:
- Genetics
- Endocrinology
- Molecular Biology
Background:
- Loss-of-function mutations in the melanocortin-4 receptor (MC4R) are the primary genetic cause of monogenic obesity.
- Monogenic obesity is a severe form of early-onset obesity with significant health implications.
Purpose of the Study:
- To determine the prevalence of MC4R mutations in Argentinian children experiencing early-onset obesity.
- To functionally characterize novel MC4R mutations identified in this cohort.
Main Methods:
- Screening of 97 Argentinian children with early-onset obesity for MC4R mutations.
- Functional analysis of identified mutations (p.V52E and p.G233S) in HEK293T cells.
- Assessment of plasma membrane expression, agonist-induced cAMP responses, and G-protein signaling pathways.
Main Results:
- Two novel MC4R mutations, p.V52E and p.G233S, were identified, with an estimated prevalence of 2.1% in the studied cohort.
- Both mutant MC4R proteins showed reduced plasma membrane expression and impaired agonist-induced cAMP signaling.
- The MC4R G233S mutant exhibited altered regulation of voltage-gated calcium channels and potentially involved a different G-protein pathway.
Conclusions:
- The study identified new MC4R mutations contributing to monogenic obesity in Argentinian children.
- Functional characterization provides insights into the molecular mechanisms underlying MC4R dysfunction.
- These findings aid in the diagnosis and potential therapeutic strategies for monogenic obesity.
Abstract:
Loss-of-function mutations in melanocortin-4 receptor (MC4R) are the most common cause of monogenic obesity, a severe type of early-onset obesity. Our aim was to determine the prevalence of MC4R mutations in a cohort of 97 Argentinian children with early-onset obesity. We found two novel mutations (p.V52E and p.G233S) and estimated a prevalence of 2.1%. We investigated the pathogenicity of mutations in HEK293T cells expressing wild-type or mutant MC4R and found that both mutants exhibited reduced plasma membrane expression and altered agonist-induced cAMP responses, with no changes in basal activity. Besides, MC4R G233S mutant demonstrated an altered agonist-dependent inhibition of voltage-gated calcium channels type 2.2. Results using a Gαs protein inhibitor suggest that the G233S mutation could be recruiting a different G-protein signaling pathway. The identification of new mutations in MC4R and characterization of their functional impact provide tools for the diagnosis and treatment of monogenic obesity.
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