Functional alterations of two novel MC4R mutations found in Argentinian pediatric patients with early onset obesity

ESTEFANÍA FERNANDEZ; SILVIA SUSANA RODRIGUEZ; VERONICA GARRIDO; RAMIRO HÉCTOR CERVIÑO; JULIETA HERNANDEZ; JESICA RAINGO; CLARA INÉS MCCARTHY; AGUSTÍN YANEFF; FLORENCIA DI ROCCO

SSRN- Electronic Journal

Elsevier

Año: 2022

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 69 Argentinian children with early-onset obesity. We found two novel mutations (p.V52E and p.G233S) and estimated a prevalence of 2.9 %. We investigated the pathogenicity of wild-type and mutated MC4R-expressing variants in HEK293T cells and found that both mutants exhibited reduced plasma membrane expression and altered agonist-induced cAMP responses, with no changes in basal activity. Results show that MC4R G233S presents 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 and the study of their impact on the functionality of MC4R provide tools for the diagnosis and treatment of the disease.