Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension

Morgane Baron; Julie Maillet; Marlène Huyvaert; Aurélie Dechaume; Raphael Boutry; Hélène Loiselle; Emmanuelle Durand; Bénédicte Toussaint; Emmanuel Vaillant; Julien Philippe; Jérémy Thomas; Amjad Ghulam; Sylvia Franc; Guillaume Charpentier; Jean-Michel Borys; Claire Lévy-Marchal; Maïthé Tauber; Raphaël Scharfmann; Jacques Weill; Cécile Aubert; Julie Kerr-Conte; François Pattou; Ronan Roussel; Beverley Balkau; Michel Marre; Mathilde Boissel; Mehdi Derhourhi; Stefan Gaget; Mickael Canouil; Philippe Froguel; Amélie Bonnefond

doi:10.1038/s41591-019-0622-0

Journal articles

Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension

Morgane Baron ¹ Julie Maillet ¹ Marlène Huyvaert ¹ Aurélie Dechaume ¹ Raphael Boutry ¹ Hélène Loiselle ¹ Emmanuelle Durand ¹ Bénédicte Toussaint ¹ Emmanuel Vaillant ¹ Julien Philippe ¹ Jérémy Thomas ² Amjad Ghulam ² Sylvia Franc ^{3, 4} Guillaume Charpentier ^{4, 3} Jean-Michel Borys ⁵ Claire Lévy-Marchal ⁶ Maïthé Tauber ⁷ Raphaël Scharfmann ⁸ Jacques Weill ⁹ Cécile Aubert ¹⁰ Julie Kerr-Conte ¹¹ François Pattou ¹¹ Ronan Roussel ^{12, 13, 14} Beverley Balkau ¹⁵ Michel Marre ^{13, 16} Mathilde Boissel ¹ Mehdi Derhourhi ¹ Stefan Gaget ¹ Mickael Canouil ¹ Philippe Froguel ^{1, 17, *} Amélie Bonnefond ^{1, 17, *}

* Corresponding author

1 GI3M - Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283

2 Centre de Biologie Pathologie - Laboratoire de Biochimie et Hormonologie [CHRU LIlle]

3 Service de Diabétologie [Orsay, Corbeil-Essonnes]

4 CERITD - Centre d'Etudes et de Recherches pour l'Intensification du Traitement du Diabète

5 FLVS - Association "Fleurbaix Laventie Ville Santé"

6 Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques Hopital Robert Debre

7 CPTP - Centre de Physiopathologie Toulouse Purpan

8 IC UM3 (UMR 8104 / U1016) - Institut Cochin

9 Service d'endocrinologie pédiatrique [CHU Lille]

10 Ildys Foundation [Roscoff, France]

11 RTD - Recherche translationnelle sur le diabète - U 1190

12 Départment de Diabétologie, Endocrinologie et Nutrition [AP-HP Hôpital Bichat]

13 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers

14 Université Paris Diderot - Paris 7 - UPD7 - UFR de Médecine - Sorbonne Paris Cité

15 CESP - Centre de recherche en épidémiologie et santé des populations

16 CMC Ambroise Paré [Neuilly-sur-Seine, France]

17 Section of Genomics of Common Disease - Department of Metabolism [London, UK]

Abstract : The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor1. Although some MRAP2 mutations have been described in people with obesity1-3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance4. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Genetics

Life Sciences [q-bio] / Human health and pathology

Life Sciences [q-bio] / Human health and pathology / Endocrinology and metabolism

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