MC4R haploinsufficiency clearly segregates with higher BMI; however, severe obesity is not fully penetrant even in MC4R LOF carriers, suggesting critical roles for environmental and lifestyle factors in MC4R monogenic obesity.
Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), or MC4R genes, have been shown to cause early-onset severe obesity.
Among 73 children with severe obesity (BMI SDS > 3.0), we identified 22 probands and 5 relatives, carrying 10 different loss-of-function homozygous mutations in LEP, leptin receptor (LEPR), and MC4R genes, including 4 novel variants.
Overall, this study suggest that S127L may be the most frequent functional MC4R mutation leading to the severe obesity in general population and provides new insight into the functionality of population based variants of the MC4R.
Melanocortin 4 receptor (MC4R) is a key factor in regulating energy homeostasis, and null mutations occurring in the gene encoding MC4R cause severe early-onset morbid obesity in humans.
We have assessed the incidence of LEP and MC4R mutations and associated hormonal profiles, in a cohort of randomly selected Pakistani children with early onset of severe obesity.
MC4R mutation analysis in a cohort of 77 children with morbid obesity identified previously unreported heterozygous mutations (P272L, N74I) in two patients inherited from their obese mothers.
The objectives of this study were to determine if mutations impairing the function of MC4R or MC3R were associated with severe obesity in North American adults.
Fifty-one unrelated probands with early onset severe obesity (body mass index (BMI) > 99th percentile; 21 girls, mean age 10.6 +/- 3.6 years) were analyzed for nucleotide variations in the MC4R coding region, by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method followed by direct DNA sequencing.