Novel Mutations in the MC2R Gene in a Patient With Familial Glucocorticoid Deficiency (FGD): A Case Report and Functional Study.

PURPOSE: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by resistance to adrenocorticotropic hormone (ACTH), leading to isolated glucocorticoid deficiency. This study aims to identify the genetic basis of FGD in a Chinese patient and investigate the functional consequences of the detected MC2R mutations.

METHODS

Whole-exome sequencing was performed to detect pathogenic variants in the MC2R gene. The effects of these mutations on MC2R mRNA and protein levels were analyzed using qPCR and immunoblotting. Additionally, a luciferase reporter assay was conducted to evaluate ACTH-induced cyclic adenosine monophosphate (cAMP) signaling.

RESULTS

The patient was found to carry compound heterozygous mutations in MC2R (p.Leu151Pro and p.Glu28*), inherited from the father and mother, respectively. Functional studies revealed that these mutations led to reduced MC2R mRNA and protein expression. Furthermore, the luciferase assay demonstrated that these variants attenuated ACTH-induced cAMP signaling.

CONCLUSION

Novel pathogenic mutations in the MC2R gene were identified, and their functional impact was characterized. These findings provide insights into the molecular mechanisms underlying FGD and contribute to the expanding genetic spectrum of the disease.