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Abstract
Recent studies reported an impact of the melanocortin 3 receptor (MC3R) on the regulation of body weight, linear growth and puberty timing. Previously, allele p.44Ile of a frequent non-synonymous variant (NSV) p.Val44Ile was reported to be associated with decreased lean body mass (LBM) and later puberty in both sexes. We Sanger sequenced the coding region of MC3R in 185 children or adolescents with short normal stature (SNS) or 258 individuals with severe obesity, and 192 healthy-lean individuals. Eleven variants (six NSVs) were identified. In-silico analyses ensued. Three rare loss-of-function (LoF) variants (p.Phe45Ser, p.Arg220Ser and p.Ile298Ser) were only found in severely obese individuals. One novel highly conserved NSV (p.Ala214Val), predicted to increase protein stability, was detected in a single lean female. In the individuals with SNS, we observed deviation from Hardy–Weinberg Equilibrium (HWE) (p = 0.012) for p.Val44Ile (MAF = 11.62%). Homozygous p.44Ile carriers with SNS had an increased BMI, but this effect did not remain significant after Bonferroni correction. In line with previous findings, the detected LoF NSVs may suggest that dysfunction in MC3R is associated with decreased body height, obesity and delayed puberty.
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1 University Hospital Essen, University of Duisburg-Essen, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Essen, Germany (GRID:grid.410718.b) (ISNI:0000 0001 0262 7331); University Hospital Essen, University of Duisburg-Essen, Center for Translational Neuro- and Behavioral Sciences, Essen, Germany (GRID:grid.410718.b) (ISNI:0000 0001 0262 7331)
2 Kiel University, Institute of Medical Informatics and Statistics, Kiel, Germany (GRID:grid.9764.c) (ISNI:0000 0001 2153 9986)
3 Justus Liebig University, Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Giessen, Germany (GRID:grid.8664.c) (ISNI:0000 0001 2165 8627)