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Obesity due to melanocortin-4 receptor (MC4R) deficiency is a monogenic form of early-onset obesity characterized by complete loss of MC4R function and inherited in an autosomal recessive manner. Four pediatric patients homozygous or compound heterozygous for loss-of-function MC4R mutations have been described, each presenting with severe obesity before school age and lacking functional receptor activity on biochemical assays (4 probands) (PMID:26538186).
Genetic evidence is limited by the small number of unrelated homozygous cases and absence of extended segregation data, but the consistent genotype–phenotype correlation across distinct families supports a causal role. No additional affected relatives with co-segregating variants have been reported (0 segregations). A recurrent homozygous null frameshift, c.750_751del (p.Ile251fs), has been documented in two siblings with complete absence of MC4R activity (PMID:15126516).
MC4R variant spectrum includes nonsense, frameshift, and missense alleles that abrogate receptor expression or signaling. Functional characterization in heterologous cells demonstrates that truncation mutants fail to bind ligand or stimulate cAMP, and are retained intracellularly due to disrupted cell-surface targeting (PMID:10585465). Hypomorphic alleles impair constitutive activity and ligand responsiveness to varying degrees, confirming loss-of-function as the predominant mechanism.
Experimental evidence from over 50 natural MC4R variants reveals impaired receptor trafficking, reduced ligand binding, and diminished cAMP generation without dominant-negative effects on co-expressed wild-type receptor. Animal models carrying analogous Mc4r mutations recapitulate hyperphagia and obesity, further corroborating the pathogenic mechanism.
Some MC4R polymorphisms (e.g., Val103Ile, Thr112Met) are functionally neutral or even protective against obesity, highlighting the necessity of functional assays to distinguish pathogenic from benign variation. No study has refuted the link between complete MC4R deficiency and severe obesity, although phenotypic expressivity may vary.
In summary, autosomal recessive MC4R deficiency causes severe early-onset obesity through complete loss of receptor signaling. While genetic evidence is limited by few homozygous cases, robust functional and animal data define a clear loss-of-function mechanism. Genetic testing for biallelic MC4R mutations informs diagnosis and guides consideration of therapeutic interventions such as bariatric surgery.
Key Take-Home: Biallelic MC4R loss-of-function mutations cause definitive receptor deficiency obesity, and functional assays are essential to confirm pathogenicity and inform clinical management.
Gene–Disease AssociationLimited4 homozygous or compound heterozygous probands; no extended segregation; consistent phenotype ([PMID:26538186]) Genetic EvidenceLimited4 probands with biallelic loss-of-function variants; no additional segregations reported Functional EvidenceModerateMultiple in vitro assays and animal models show loss of MC4R signaling and cell-surface expression consistent with human obesity |