MC2R – Familial Glucocorticoid Deficiency

Familial glucocorticoid deficiency (FGD; MONDO:0008733) is an uncommon autosomal recessive disorder characterized by isolated cortisol deficiency and elevated plasma ACTH due to insensitivity of the adrenal cortex to ACTH. MC2R (HGNC:6930) encodes the melanocortin-2 (ACTH) receptor, and pathogenic biallelic MC2R variants account for approximately 25% of FGD cases.

Genetic evidence supports a definitive gene–disease association: 107 unrelated probands harboring MC2R variants have been reported, including 59 distinct alleles comprising predominantly missense substitutions as well as frameshift, nonsense, and splice-site changes (PMID:32952553). Among these, c.221G>T (p.Ser74Ile) is a recurrent missense variant observed in multiple families. Founder effects have been documented for c.560delT in Iranian cohorts (PMID:39135905).

Segregation analysis in consanguineous and non-consanguineous families confirms autosomal recessive inheritance with concordant segregation in at least 19 affected relatives (PMID:8094489). Carriers are asymptomatic, consistent with loss-of-function alleles requiring biallelic inactivation.

Functional studies demonstrate that many MC2R mutants fail to traffic to the cell surface and have abolished or severely reduced cAMP responses to ACTH stimulation. For example, p.Ser74Ile and p.Tyr254Cys show no measurable receptor activity in cAMP reporter assays, and C-terminal frameshift K289fs abolishes receptor localization despite intact MRAP interaction (PMID:12213892; PMID:20962024). These data indicate a loss-of-function mechanism underlying FGD type 1.

Although MC2R variants explain a quarter of FGD, linkage and mutation analyses have identified additional loci (MRAP, STAR, NNT, MCM4, etc.) in the remainder, underscoring genetic heterogeneity. Lack of MC2R defects in some FGD families highlights the importance of comprehensive genetic testing.

Key Take-home: Biallelic MC2R loss-of-function variants cause autosomal recessive FGD type 1; early molecular diagnosis enables prompt glucocorticoid replacement, prevents hypoglycaemic and infectious complications, and guides family counselling.

References

• International Journal of Endocrinology • 2020 • The Genetic Perspective of Familial Glucocorticoid Deficiency: In Silico Analysis of Two Novel Variants. PMID:32952553
• The Journal of Clinical Endocrinology and Metabolism • 2002 • Clinical, genetic, and functional characterization of adrenocorticotropin receptor mutations using a novel receptor assay. PMID:12213892
• The Journal of Clinical Endocrinology and Metabolism • 2011 • Loss of the C terminus of melanocortin receptor 2 (MC2R) results in impaired cell surface expression and ACTH insensitivity. PMID:20962024
• International Journal of Endocrinology • 2024 • Expanding the Phenotype of Congenital Glucocorticoid Deficiency: An Iranian Patient with Cholestasis due to Pathogenic Variants in the MC2R Gene. PMID:39135905
• Lancet • 1993 • Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor. PMID:8094489

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