MC2R – Familial Glucocorticoid Deficiency Type 1

Familial glucocorticoid deficiency type 1 (FGD1) is an autosomal recessive disorder caused by biallelic loss-of-function variants in MC2R, the ACTH receptor expressed in the adrenal cortex. Affected individuals present with low or undetectable serum cortisol, markedly elevated ACTH, hypoglycemia, seizures, skin hyperpigmentation, hyperbilirubinemia, cholestasis, and tall stature, often with dysmorphic features such as hypertelorism, prominent forehead, and a broad nasal bridge ([PMID:31244773]).

MC2R-associated FGD1 follows an autosomal recessive inheritance pattern with extensive genetic heterogeneity. To date, 107 probands (85 homozygotes, 21 compound heterozygotes, 1 heterozygote) have been reported carrying 59 distinct MC2R variants ([PMID:32952553]). Segregation of a novel homozygous c.326T>A (p.Leu109Gln) variant in two siblings confirmed recessive inheritance ([PMID:35506146]). Additionally, five Arab kindreds share a recurrent c.459dupC (p.Ile154HisfsTer?) frameshift variant ([PMID:21778684]).

The MC2R variant spectrum comprises predominantly missense changes with additional frameshift/nonsense, splice-site, and a non-coding promoter deletion. In aggregate, 50 missense, 6 frameshift/nonsense, 3 splice, and 1 large promoter deletion variants have been documented in FGD1 ([PMID:32952553]). No widely distributed founder alleles have been identified outside consanguineous populations.

Functional studies demonstrate a loss-of-function mechanism via defective receptor folding, trafficking, or signaling. In vitro expression of p.Ser74Ile and p.Pro273His in melanoma cells showed markedly reduced cAMP responses to ACTH, confirming impaired signal transduction ([PMID:9758716]). Luciferase reporter assays in ACTH-unresponsive OS-3 cells revealed negligible activity for R137W, p.Tyr254Cys, and other mutants, establishing functional concordance with human phenotypes ([PMID:12213892]). Co-expression with MRAP rescues membrane localization for select variants, underscoring its role in MC2R trafficking.

Rare activating or regulatory variants do not dispute the MC2R–FGD1 association but illustrate receptor regulation complexity. A double mutant p.Cys21Arg/p.Ser247Gly exhibited constitutive cAMP signaling in Y6 cells without clinical hypercortisolism ([PMID:15062562]). A promoter polymorphism (CCC/CCC) reduces ACTH responsiveness in healthy subjects, highlighting regulatory elements outside coding regions ([PMID:15240582]).

In summary, MC2R mutations have a definitive association with FGD1, supported by extensive genetic and functional evidence. Molecular diagnosis of MC2R variants enables targeted hydrocortisone replacement, prevents life-threatening hypoglycemic crises, and informs family counseling.

References

• Frontiers in endocrinology • 2019 • Novel Melanocortin 2 Receptor Variant in a Chinese Infant With Familial Glucocorticoid Deficiency Type 1, Case Report and Review of Literature [PMID:31244773]
• International journal of endocrinology • 2020 • The Genetic Perspective of Familial Glucocorticoid Deficiency: In Silico Analysis of Two Novel Variants [PMID:32952553]
• Journal of the Endocrine Society • 2022 • A Novel Homozygous MC2R Variant Leading to Type-1 Familial Glucocorticoid Deficiency [PMID:35506146]
• Hormone research in paediatrics • 2011 • Familial glucocorticoid deficiency in five Arab kindreds with homozygous point mutations of the ACTH receptor (MC2R): genotype and phenotype correlations [PMID:21778684]
• Molecular genetics and metabolism • 1998 • Genetic heterogeneity of adrenocorticotropin (ACTH) resistance syndromes: identification of a novel mutation of the ACTH receptor gene in hereditary glucocorticoid deficiency [PMID:9758716]
• The Journal of clinical endocrinology and metabolism • 2002 • Clinical, genetic, and functional characterization of adrenocorticotropin receptor mutations using a novel receptor assay [PMID:12213892]
• Molecular and cellular endocrinology • 2004 • Constitutive activation of the human ACTH receptor resulting from a synergistic interaction between two naturally occurring missense mutations in the MC2R gene [PMID:15062562]
• The Journal of clinical endocrinology and metabolism • 2004 • Characterization of an adrenocorticotropin (ACTH) receptor promoter polymorphism leading to decreased adrenal responsiveness to ACTH [PMID:15240582]

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