ESPEYB17 11. Obesity and Weight Regulation New Genetic Findings (2 abstracts)
11.2. Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension
Baron M , Maillet J , Huyvaert M , Dechaume A , Boutry R , Loiselle H , Durand E , Toussaint B , Vaillant E , Philippe J , Thomas J , Ghulam A , Franc S , Charpentier G , Borys JM , Lévy-Marchal C , Tauber M , Scharfmann R , Weill J , Aubert C , Kerr-Conte J , Pattou F , Roussel R , Balkau B , Marre M , Boissel M , Derhourhi M , Gaget S , Canouil M , Froguel P & Bonnefond A
NRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, University of Lille, Lille, France;
Department of Metabolism, Section of Genomics of Common Disease, Imperial College London, London UK. p.froguel@imperial.ac.uk
To read the full abstract: Nature Medicine. 2019;25(11):1733–8. PMID 31700171.
These authors sequenced the gene for melanocortin-2 receptor accessory protein (MRAP2 ) in 9418 blood DNA samples from several population studies. They detected 23 rare heterozygous variants, which were significantly associated with an increased risk of obesity (OR 3.8 in children and 2.9 in adults). More so, functional analysis revealed a loss of function for 6 variants, with significantly decreased cAMP-PKA signalling in vitro in response to α-MSH and ACTH, and these variants showed a complete penetrance for obesity/overweight. In addition, affected carriers also showed a high rate of hyperglycemia and hypertension – in contrast to carriers of other forms of monogenic obesity. None of the carriers showed hypoadrenalism.
Data in rodents and humans have previously indicated that gene coding variants in MRAP2 are associated with obesity (1, 2). With an increasing worldwide prevalence of obesity, it is of great interest to understand the genetic background of obesity. Rare variants in over 15 genes have been identified so far, which are believed to be causal for monogenic obesity. However, evidence especially for autosomal dominant variants are equivocal. Functional testing of new variants even in well-established obesity genes is hence mandatory, to ascertain their causal role in the development of obesity. This is illustrated best by variants in the MC4 receptor gene where proven loss of function variants confer an increased risk for obesity, gain of function variants are protective against obesity (see paper 11.3), and some rare non-synonymous variants have no measurable effect at all. Hence this thorough examination of the functional impact of MRAP2 variants helps to ascertain their causal role in the development of obesity. Very interesting is also the detailed comparison to reported rates of co-morbidities in other forms of monogenic obesity which indicates that variants in MRAP2 might influence more than just body-weight.
References:
1. Asai M, Ramachandrappa S, Joachim M, Shen Y, Zhang R, Nuthalapati N, et al. Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science (New York, NY). 2013;341 (6143):275–8.
2. Schonnop L, Kleinau G, Herrfurth N, Volckmar AL, Cetindag C, Müller A, et al. Decreased melanocortin-4 receptor function conferred by an infrequent variant at the human melanocortin receptor accessory protein 2 gene. Obesity (Silver Spring, Md). 2016;24 (9):1976–82.
3. Lotta LA, Mokrosinski J, Mendes de Oliveira E, Li C, Sharp SJ, Luan J, et al. Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity. Cell. 2019;177 (3):597–607.e9.
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ESPE Yearbook of Paediatric Endocrinology
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