Identification and molecular characterization of missense mutations in orphan GPCR GPR61 occurring in severe obesity

Obesity is a disease defined as “abnormal or excessive fat accumulation that presents a health risk, with a body mass index (BMI) over 30” (World Health Organization). Signalling mediated by hypothalamus-expressed membrane proteins from the GPCR family regulates food intake and metabolism. The orphan GPCR GPR61 was linked to regulation of metabolism and, here, we identify 34 mutations in the GPR61 gene which are present with much higher frequency in severe obesity samples from UK10K obesity screen than in the normal population. The cumulative sum of mutations was higher for the GPR61 gene compared to the highly mutated and well-established target, melanocortin 4 receptor (MC ₄ R). The majority of the GPR61 mutations reduced cell surface expression of overexpressed HiBiT-GPR61 in HEK293A cells. Additionally, the mutations T92P, R236C and R262C reduced ligand-independent GPR61-induced cAMP production, and R236C compromised G _s protein activation. Therefore, we suggest that GPR61 indeed represents a G _s -coupled receptor with a potential role in the regulation of metabolism. Our data warrant further studies to assess role of this orphan GPCR in metabolism in greater detail.