Mutations in the MRAP2 gene may increase the risk for obesity, high blood sugar, and hypertension, a large genetic study has found.
The study, “Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension,” was published in the journal Nature Medicine.
Loss-of-function mutations disrupt the function of the resulting protein. In the case of MRAP2, such mutations have been associated with obesity in mice. The same study found four rare variants in this gene among 976 people with severe obesity and none in the controls, but it did not analyze the function of the altered proteins.
The MRAP2 protein (melanocortin-2 receptor accessory protein 2) is known to increase the activity of another protein, called MC4R (melanocortin 4 receptor). Importantly, mutations in the MC4R gene have been found to constitute the most frequent single genetic cause of obesity.
Researchers in France conducted a large-scale sequencing of the protein-coding portions (exons) of MRAP2 in 9,418 people — 7,239 adults and 2,179 children or adolescents — to better understand how mutations in this gene impact protein function.
Results revealed 23 rare genetic variants, 14 of which had never been reported. These variants were associated with an increased risk of obesity, 3.8-fold in adults and 2.91 times in children/adolescents.
The team then performed in vitro experiments to assess protein function. Cells expressing any of six MRAP2 mutations had decreased MC4R signaling, suggesting a link between such variants and obesity.
Seven loss-of-function variants were identified in seven obese or overweight adults of European origin and in three obese European adolescents. Most (75%) people carrying these mutations had abnormal eating behavior, including overeating.
Also, most carriers had high blood sugar (hyperglycemia) and high blood pressure (hypertension). According to the scientists, this contrasts with mutations in other obesity-related genes (such as MCR4), as the frequency of hyperglycemia and hypertension is lower in people carrying those mutations.
The researchers then used beta cells, responsible for producing the hormone insulin in the pancreas, and found that lowering the levels of MRAP2 led to decreased insulin production in those cells.
“These results suggest that MRAP2 mutations could have a direct functional deleterious [harmful] effect on beta cells,” the researchers wrote.
They suggested that effects on the receptor of the hormone grehlin (key in appetite and growth hormone release) could link changes in MRAP2 to high blood pressure.
Overall, the study suggests that mutations in MRAP2 could lead to obesity and related health problems, but medications already in development may be helpful.
“Because MRAP2 deficiency partly impacts the MC4R pathway, the eating behavior problems in people deficient in MRAP2 might be treated by the MC4R agonist setmelanotide,” the investigators wrote.