**2.4. POMC deficiency (OMIM #609734)**

In 1997, a role of central melanocortin signaling in the control of energy homeostasis was known [37]. Proopiomelanocortin (POMC) acts on anorectic targets of leptin in the brain [38]. The POMC, through to proconvertase 1 (PCSK1), is the precursor of a‐melanocyte‐stimulating‐ hormone anorectic peptide (a‐MSH); the latter acts on melanocortin 4 receptor (MC4‐R) anorectic neurons and suppresses the appetite and food intake [39].

Monogenic obesity from POMC deficiency manifests itself when there are homozygous null mutations. Heterozygous carriers of null *POMC* gene mutations have a significantly higher risk of being obese or overweight but are not invariably associated with obesity [19].

Since POMC is the precursor of adrenocorticotropic hormone (ACTH) and melanocyte‐ stimulating‐hormone anorectic peptide (MSH), POMC‐deficient newborns have adrenal crisis and pale skin and hair. Also, POMC deficiency causes hyperphagia and childhood obesity [3, 40]. The clinical features are comparable to those reported in patients with mutations in the receptor for POMC‐derived ligands, MC4R (see below in the next chapter) [12].

Two important *POMC* mutations have been described in literature: the first is the rare mutation *R236G* that disrupts a di‐basic cleavage site between β‐MSH and β‐endorphin, resulting in a β‐MSH/β‐endorphin fusion protein that binds to MC4R but has reduced ability to activate the receptor [38, 41]. The second is a rare missense mutation in the region encoding β‐MSH, *Tyr221Cys* that cannot bind to and activate signaling from the MC4R, and obese children carrying the *Tyr221Cys* variant are hyperphagic and showed increased linear growth, features of MC4R deficiency [42].

Specific treatment was not available until January 2016, when the US Food and Drug Admin‐ istration awarded orphan drug status to the first α‐MSH‐based therapy for obesity. The α‐MSH analog RM‐493 [43, 44], also known as setmelanotide, was awarded orphan drug status for POMC deficiency and Prader‐Willi syndrome [37].
