Early-onset, severe obesity and hyperphagia are clinical characteristics of rare genetic disorders of obesity due to loss-of-function (LOF) variants in genes comprising the MC4R pathway, including leptin receptor (LEPR), pro-opiomelanocortin (POMC), and proprotein convertase subtilisin/kexin type 1 (PCSK1). To improve the understanding of the functional effects that LEPR, POMC, and PCSK1 genetic variants have on individuals with early-onset, severe obesity and hyperphagia, we are performing functional characterization of all conceivable single nucleotide variants (SNVs; total- 12,880) in LEPR (6851), POMC (1577), and PCSK1 (4452).


The impact of missense variants on protein function was assessed using well established in vitro cell based assays.


A total of 3000 missense (all published variants, variants observed in major public databases, variants observed through Rhythm’s nucleotide sequencing initiatives, and some variants computationally predicted to be deleterious) have been functionally characterized so far, including 1190 in LEPR, 354 in POMC, and 1456 in PCSK1. LEPR: Out of 1190 variants, 7 % of variants were complete LOF, 22% were partial LOF, and 71% of variants exhibited wildtype like activity. POMC: Out of 354 variants, 3% variants were partial LOF, and 97% of variants exhibited wildtype like activity. PCSK1: Out of 1456 variants, 53% were complete LOF, 16% partial LOF, and 31% exhibited wildtype like activity. We are currently undertaking a functional characterization of remaining 9,880 missense variants in LEPR, POMC, and PCSK1.


These data provide new insight into the functional deleteriousness of missense mutations in three genes known to cause rare genetic disorders of obesity.