Frequency of gene mutations of the leptin / melanocortin pathway in severe obesity

Introduction and purpose of the study: The leptin / melanocortin pathway plays a critical role in hypothalamic control of food intake. Mutations on the genes of this pathway, such as leptin (LEP) and its receptor (LEPR), proopiomelanocortin (POMC), proconvertase 1 (PCSK1) are associated with early and severe obesity with endocrine abnormalities including homozygosity. Heterozygote melanocortin-like receptor (MC4R) mutations are associated with an increased risk of severe obesity. The aim is to describe the frequency of homozygous and heterozygous mutations in leptin / melanocortin pathway genes in obese children and adults attending a specialized center. Material and methods: The coding exons of the LEP , LEPR , POMC , PCSK1 and MC4R genes were sequenced by the SANGER method. The 6100 patients included had severe obesity (BMI > 35 kg / m 2 for adults and Zscore BMI > + 2.5 DS for children). MC4R was sequenced in 5815 subjects, LEPR in 1180 patients, LEP in 800 patients, POMC in 556 patients and PCSK1 in 288 patients. Results and statistical analysis: The frequency of homozygous variants was ≤1 % with 13 (1.02%) LEPR variants (p.C604G, p.L786P, p.H800_N831del, p.Y422H p.T711 N, p.535-1G > A, p. P166CfsX7, p.Met1X), 3 (0.4%) LEP variants (p.Q55X, p.R105 W, p.V94M ), 1 variant (0.4%) PCSK1 (c.286-2A > G) , 3 variants (0.6%) POMC (p.R75Profs × 44, p.E214G, p.D53G) and 7 variants (0.12%) MC4R (p.R165Q, p.S127L, p.C277X, p. V166I, p.C271R, p.I170 V). Homozygous patients had early obesity before age 3, major hyperphagia in infancy, and other associated endocrine phenotypes. The frequency of the heterozygous variants was 2-3% for POMC, MC4R and LEPR while it was less than 2% for PCSK1 (1.4%) and LEP (0.5%). The presence of a heterozygous variant with functional consequence in these genes was always associated with obesity started before 10 years without endocrine abnormality. Four patients had heterozygous variants combined on at least two channel gene ( POMC p.D53G and LEP p.V94 M [ n = 1]; LEPRp.W699 M and LEP p.V94 M [ n = 1]; MC4R p.S58 C and LEPR p.W699 M [ n = 2]) with possible cumulative effect. Conclusion: This work confirms the involvement of gene variants of the leptin / melanocortin pathway in early and severe obesity (2 to 3% of patients with severe obesity) and is currently being extended to other genes modulating this pathway. This screening is criticized because today effective therapeutic options by agonist MC4R (setmelanotide) exist and can restore the activity of this pathway (Clement et al, Nature Med, 2018). The development of diagnostic clinical tools and new molecular tests by NGS extended to other genes in the pathway will diagnose patients who are candidates for this new therapy.