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The role of common and rare MC4R variants and FTO polymorphisms in extreme form of obesity

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Abstract

Melanocortin 4 receptor (MC4R) is an important regulator of food intake and number of studies report genetic variations influencing the risk of obesity. Here we explored the role of common genetic variation from MC4R locus comparing with SNPs from gene FTO locus, as well as the frequency and functionality of rare MC4R mutations in cohort of 380 severely obese individuals (BMI > 39 kg/m2) and 380 lean subjects from the Genome Database of Latvian Population (LGDB). We found correlation for two SNPs—rs11642015 and rs62048402 in the fat mass and obesity-associated protein (FTO) with obesity but no association was detected for rs17782313 located in the MC4R locus in these severely obese individuals. We sequenced the whole gene MC4R coding region in all study subjects and found five previously known heterozygous non-synonymous substitutions V103I, I121T, S127L, V166I and I251L. Expression in mammalian cells showed that the S127L, V166I and double V103I/S127L mutant receptors had significantly decreased quantity at the cell surface compared to the wild type MC4R. We carried out detailed functional analysis of V166I that demonstrated that, despite low abundance in plasma membrane, the V166I variant has lower EC50 value upon αMSH activation than the wild type receptor, while the level of AGRP inhibition was decreased, implying that V166I cause hyperactive satiety signalling. Overall, this study suggest that S127L may be the most frequent functional MC4R mutation leading to the severe obesity in general population and provides new insight into the functionality of population based variants of the MC4R.

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Acknowledgments

This work was supported by ERDF Project No. 2010/0311/2DP/2.1.1.1.0/10/APIA/VIAA/069 and the Latvian Research Program (4VPP-2010-2/2.1). HBS was supported by the Swedish Research Council. We acknowledge the Genome Database of Latvian population, Latvian Biomedical Research and the Study Centre for providing data and DNA samples.

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  1. Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, 1067, Riga, Latvia

    Vita Rovite, Ramona Petrovska, Iveta Vaivade, Ineta Kalnina, Davids Fridmanis, Linda Zaharenko, Raitis Peculis & Janis Klovins

  2. Faculty of Medicine, University of Latvia, Sarlotes Str. 1a, Riga, 1001, Latvia

    Valdis Pirags

  3. Department of Endocrinology, Pauls Stradins Clinical University Hospital, Pilsonu Str. 13, Riga, 1002, Latvia

    Valdis Pirags

  4. Department of Neuroscience, Functional Pharmacology, Uppsala University, 751 24, Uppsala, Sweden

    Helgi B. Schioth

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  1. Vita Rovite
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Rovite, V., Petrovska, R., Vaivade, I. et al. The role of common and rare MC4R variants and FTO polymorphisms in extreme form of obesity. Mol Biol Rep 41, 1491–1500 (2014). https://doi.org/10.1007/s11033-013-2994-4

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