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A novel nonsense mutation in the melanocortin-4 receptor associated with obesity in a Spanish population

Abstract

BACKGROUND: In recent years, several groups have reported dominant inheritance of obesity conferred by missense, nonsense and frameshift mutations in the melanocortin 4 receptor gene (MC4R). Hence, MC4R is involved in the most common monogenic form of human obesity described so far.

OBJECTIVES: In this context, we screened a Spanish population, composed of obese subjects and normal weight controls, for mutations in the MC4-R by single-strand conformational polymorphism (SSCP).

SUBJECTS AND METHODS: Overall 313 individuals, 159 obese subjects (body mass index: BMI: 37.6 kg/m2, 95% CI: 36.7–38.5 kg/m2) and 154 normal weight control subjects (BMI: 22.3 kg/m2, 95% CI: 22.0–22.6 kg/m2) were screened for MC4-R mutations.

RESULTS: We detected a novel nonsense mutation at codon 16 of the MC4-R in an obese female (BMI: 30.0 kg/m2) and a previously described missense mutation (Val-253-Ile) located within the sixth trans-membrane domain of the MC4-R in a normal weight individual (BMI: 19.0 kg/m2). The polymorphism Val-103-Ile was detected in one obese individual, while four subjects (two cases and two controls) with the polymorphism Ile-251-Leu were found.

CONCLUSIONS: We have identified a novel nonsense mutation (Trp-16-Stop) that, based on previously described frameshift and nonsense mutations, most likely results in dominantly inherited obesity. Within this Spanish population, the frequency of the Ile-251-Leu polymorphism of the MC4R was similar in obese and control subjects (about 1.3%), while the polymorphism Val-103-Ile was only detected in an obese individual (0.6%).

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Acknowledgements

We thank Gerti Gerber and Mentxu Ochoa for their expertise and support. We thank all individuals for their participation. This work was supported by the Deutsche Forschungsgemeinschaft, the German Bundesministerium für Bildung und Forschung (BMBF, 01GS0118 and 01KW0006), Goverment of Navarra (Heath Department) and University of Navarra (Línea Especial Obesidad). AM received a grant for University Professor Exchange from the DAAD (Deutshe Akademische Austauschdienst) which is gratefully acknowlegded.

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Marti, A., Corbalán, M., Forga, L. et al. A novel nonsense mutation in the melanocortin-4 receptor associated with obesity in a Spanish population. Int J Obes 27, 385–388 (2003). https://doi.org/10.1038/sj.ijo.0802244

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