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PgmNr 2: Pathogenic, loss-of-function mutations in MRAP2 cause metabolic syndrome.

Authors:
A. Bonnefond 1; M. Baron 1; J. Maillet 1; M. Huyvaert 1; R. Boutry 1; G. Charpentier 2; M. Tauber 3; R. Roussel 4; B. Balkau 5; M. Marre 4; M. Canouil 1; P. Froguel 1

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Affiliations:
1) CNRS UMR8199, Lille, France; 2) CERITD (Centre d'Étude et de Recherche pour l'Intensification du Traitement du Diabète), Evry, France; 3) Inserm UMR1043, Toulouse, France; 4) Inserm U1138, Centre de Recherche des Cordeliers, Paris, France; 5) Inserm U1018, Center for Research in Epidemiology and Population Health, Villejuif, France


The G-protein-coupled receptor (GPCR) accessory protein MRAP2 was reported to be involved in rodent energy control. Notably, it was shown that MRAP2 interacted directly with the obesity gene MC4R, and enhanced MC4R downstream signaling, suggesting that this mechanism linked Mrap2 deficiency and rodent obesity. Although a couple of mutations in MRAP2 were described in few obese human subjects, their functional consequences and their putative impact on obesity have remained elusive. Here, we performed a large-scale resequencing study of MRAP2 in 9,418 participants, in combination with functional assays of detected variants, to accurately decipher the functional link between MRAP2 and obesity (and possibly associated phenotypes) in humans. We identified 23 rare variants (with a minor allele frequency between 0.0053 and 0.17%) that were significantly associated with increased obesity risk, in both adults and children. After functional assessment of each variant, we found that 7 pathogenic, loss-of-function MRAP2 variants were totally penetrant for overweight or obesity in both adults and children. Surprisingly, when we investigated the clinical data of the carriers, we found that they actually had metabolic syndrome. In addition to high adiposity, this genetic form of metabolic syndrome was mainly associated with hyperglycemia (88% of carriers) and hypertension (71% of carriers). This is remarkable as only 30-60% of obese people present with metabolic syndrome. Importantly, MRAP2-deficient obese subjects are different from MC4R-deficient obese subjects who do not present with any other metabolic clinical features, with particularly low blood pressure. Through expression analysis of MRAP2 in a panel of human tissues, we surprisingly found that the high expression of MRAP2 was similar in brain regions and in human pancreatic islets and beta cells. We also discovered that MRAP2 knockdown in human beta cells significantly decreased insulin secretion. As we also found that MRAP2 was expressed in key metabolic tissues including gut, kidney, muscle and fat, we suggest that MRAP2 deficiency causes combined metabolic abnormalities in humans possibly due to the failure of different GPCRs signaling (co)regulated by MRAP2 (such as ghrelin receptor). To our knowledge, it is only the second description of a monogenic form of metabolic syndrome, after the identification of DYRK1B deficiency few years ago, showing that complex metabolic phenotypes can be genetically driven.