Abstract
Screening 92,445 subjects in the Geisinger-Regeneron DiscovEHR cohort, we identified 5 patients heterozygous for nonsense mutations causing early terminations at Glu307 or Leu328 on the C-terminus of melanocortin 4 receptor (MC4R). Two Q307Ter carriers are severely obese (BMI > 40), while one is overweight (BMI > 25). One L328Ter carrier is overweight and the other is lean. Pedigree analysis for two Q307Ter carriers shows segregation of the variant with higher BMI. Functionally, MC4R(Q307Ter) eliminated receptor surface expression and signaling, while MC4R(L328Ter) functioned like the wild-type receptor. MC4R(Q307Ter) is therefore a loss of function (LOF) variant and the region between the two truncation sites identified in our patients is critical to MC4R function. Truncating MC4R at various C-terminal positions between these two variant sites, we find that cysteine318 sits at a critical junction for receptor trafficking and function. We show that MC4R is lipid modified at cysteine318 and cysteine319. Therefore, truncation early in the MC4R C-terminus results in haploinsufficiency in humans while truncation after the first lipid-modification site is well tolerated. 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.
Highlights
Obesity is a worldwide epidemic that contributes to comorbidities such as diabetes and cardiovascular disease[1]
Using whole exome sequencing data linked to longitudinal electronic health records from 92,445 participants in the Geisinger-Regeneron DiscovEHR project, we have found three participants that are heterozygous for truncation at Q307 and two that are heterozygous for truncation at L328 in melanocortin 4 receptor (MC4R)
Through whole exome sequencing of 92,445 participants in the MyCode cohort as part of the Geisinger-Regeneron DiscovEHR project, we found five participants heterozygous for early termination variants in the C-terminus of MC4R: three at Glutamine 307 (Q307Ter)
Summary
Obesity is a worldwide epidemic that contributes to comorbidities such as diabetes and cardiovascular disease[1]. Satiety signals (α-MSH) released from pro-opiomelanocortin neurons and feeding signals (AgRP) released from agouti-related protein neurons are ligands for the melanocortin 4 receptor (MC4R)[3] Since it receives both feeding and satiety signals, MC4R critically regulates feeding behavior and energy homeostasis. An in vitro study has shown that truncation of MC4R after cysteine 319 results in a functional receptor[6] It remains unclear why the region between K314 and C319, the 315EIICC319 region, encompassing part of the putative 8th helical region of the MC4R C-terminus, is critical for receptor function. Cell surface expression and function and narrow down the essential amino acids in the C-terminus of MC4R to maintain function Based on these functional data we have determined a critical role of the C-terminus of MC4R in its trafficking, function and demonstrate a mechanistic link to human obesity
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