These effects are pronounced when mutations occur in a bi-allelic manner for LEP, LEPR, PCSK1 and POMC, or in a homozygous or heterozygous state for MC4R. We have recently shown that total loss-of-function heterozygous mutations in PCSK1 were also able to cause monogenic obesity [18]. This evidence concerns the gene LEP and obesity due to melanocortin 4 receptor deficiency.