POMC – inherited obesity

Autosomal recessive POMC deficiency is a rare cause of early‐onset obesity, and heterozygous POMC variants have been implicated in inherited obesity. Five unrelated probands harboring heterozygous missense variants in POMC were reported: two carriers of c.706C>G (p.Arg236Gly) co‐segregating with early‐onset obesity over three generations (3 affected relatives) (PMID:12165561), one carrier of c.432C>G (p.Phe144Leu) transmitted from an affected father (PMID:18091355), and two carriers of c.83G>T (p.Cys28Phe) and c.109C>T (p.Leu37Phe) in unrelated early‐onset obese probands (PMID:18697863). A population screen of 102 morbidly obese Swedish subjects found no POMC coding mutations, suggesting rarity and variable penetrance (PMID:14513068).

Functional assays provide concordant evidence of pathogenicity: the p.Arg236Gly variant disrupts a dibasic processing site, producing a fusion peptide that binds MC4R but fails to activate cAMP signaling (PMID:12165561), while the p.Cys28Phe and p.Leu37Phe mutants impair sorting to the regulated secretory pathway and reduce generation of bioactive POMC‐derived peptides (PMID:18697863). These data support a mechanism of haploinsufficiency or dominant‐negative interference in heterozygous carriers. Key Take‐home: Rare heterozygous POMC missense variants can predispose to inherited obesity, warranting targeted genetic testing in early‐onset cases.

References

• Human molecular genetics • 2002 • A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. PMID:12165561
• Pediatric research • 2008 • Mutational analysis of the pro-opiomelanocortin gene in French obese children led to the identification of a novel deleterious heterozygous mutation located in the alpha-melanocyte stimulating hormone domain. PMID:18091355
• The Journal of clinical endocrinology and metabolism • 2008 • Mutations in the amino-terminal region of proopiomelanocortin (POMC) in patients with early-onset obesity impair POMC sorting to the regulated secretory pathway. PMID:18697863
• International journal of obesity • 2003 • Pro-opiomelanocortin gene is associated with serum leptin levels in lean but not in obese individuals. PMID:14513068

Evidence Based Scoring (AI generated)