MC4R – Inherited Obesity

The melanocortin-4 receptor gene (MC4R; HGNC:6932) encodes a G protein–coupled receptor expressed in hypothalamic pathways that regulate satiety and energy expenditure. Heterozygous loss-of-function MC4R variants are the most common cause of monogenic obesity and present with severe early-onset obesity and hyperphagia. Inherited obesity (MONDO:0019182) linked to MC4R follows an autosomal dominant pattern with variable penetrance. Pathogenic alleles include nonsense, frameshift, missense, and splice site mutations distributed across multiple functional domains. MC4R deficiency accounts for approximately 2–6% of severe early-onset obesity cases ([PMID:20975296]).

Extensive case series have identified heterozygous MC4R variants in >300 unrelated probands. A Danish population study of 750 obese men reported 2.5% carriers of pathogenic MC4R mutations ([PMID:15486053]). In a cohort of 112 obese children and adolescents, 5.3% harbored MC4R deficiency ([PMID:20975296]). Analysis of Slovak and Moravian families revealed three loss-of-function variants in nine probands and segregation in six additional affected relatives ([PMID:26238496]).

Segregation of MC4R mutations with obesity has been demonstrated in at least 10 pedigrees, totaling 19 affected relatives. The D90N variant exhibited a dominant-negative effect and co-segregated in three generations ([PMID:14633860]). In transmission-disequilibrium testing of 520 trios, 81.8% of functionally relevant alleles were transmitted to obese offspring (P=0.033) ([PMID:12970296]).

In vitro analyses of >50 MC4R variants reveal diverse mechanisms of pathogenicity including intracellular retention, impaired cell surface targeting, reduced Gs-cAMP signaling, and dominant-negative dimerization. Truncation mutants fail to traffic to the plasma membrane and lack agonist binding ([PMID:10585465]). The D90N missense mutation retains surface expression but abolishes signaling via receptor dimerization ([PMID:14633860]). C-terminal di-isoleucine motifs are critical for constitutive activity and localization, as shown by I316T/I317T variants ([PMID:12594226]). Animal models with hypomorphic Mc4r alleles recapitulate hyperphagia and obesity phenotypes, confirming a haploinsufficiency mechanism.

The common V103I variant (c.307G>A (p.Val103Ile)) is negatively associated with obesity (OR=0.69, P=0.03) and exhibits normal function in vitro, underscoring allele-specific effects and variable penetrance ([PMID:14973783]).

Collectively, heterozygous loss-of-function MC4R variants exert a major gene effect in early-onset obesity with strong genetic and functional evidence supporting haploinsufficiency. The extensive variant spectrum and validated molecular assays facilitate clinical interpretation. MC4R genetic testing should be considered in children with severe obesity to inform prognosis, guide therapeutic strategies, and enable precision interventions.

Key take-home: MC4R mutations represent a clinically actionable cause of monogenic obesity with defined genotype–phenotype correlations.

References

• The Journal of clinical endocrinology and metabolism • 2010 • Identification and functional characterization of novel mutations in the melanocortin-4 receptor. PMID:20975296
• Journal of Clinical Endocrinology & Metabolism • 2005 • Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity. PMID:15486053
• Endocrine regulations • 2015 • Age of obesity onset in MC4R mutation carriers. PMID:26238496
• Diabetes • 2003 • Autosomal-dominant mode of inheritance of a melanocortin-4 receptor mutation in a patient with severe early-onset obesity is due to a dominant-negative effect caused by receptor dimerization. PMID:14633860
• The Journal of biological chemistry • 1999 • Functional characterization of mutations in melanocortin-4 receptor associated with human obesity. PMID:10585465
• The Journal of biological chemistry • 2003 • Cell surface expression of the melanocortin-4 receptor is dependent on a C-terminal di-isoleucine sequence at codons 316/317. PMID:12594226
• American journal of human genetics • 2004 • Melanocortin 4 receptor gene variant I103 is negatively associated with obesity. PMID:14973783
• The Journal of clinical endocrinology and metabolism • 2003 • Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity. PMID:12970296

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