MC4R Mutations Research Articles

Functional Characterization of MC4R Variants in Chinese Morbid Obese Patients and Weight Loss after Bariatric Surgery.

Mutations in MC4R are the most common genetic cause of obesity. In the reported Chinese morbid obesity cohort, 10 out of 59 harbor six MC4R variants, including Y35C, T53I, V103I, R165W, G233S, and C277X, among which V103I has a relatively high frequency, while other five variants are rare in the population. The prevalence of MC4R carriers in Chinese morbid obese patients (body mass index≥ 45kg m-2 ) is detected as 16.9% in this study. R165W and C277X are loss-of-function variants. The patient with R165W achieves excess weight loss (%EWL) as high as 20.6% and 50.3% at 1 and 8 months after surgery, respectively. G233S is reported for the first time in Asia obese population. The patient harboring G233S has a %EWL as 23.3% one month postsurgery. It is concluded that morbid obese patients with rare MC4R variants can benefit from metabolic surgery. More importantly, the choice of surgery procedure and MC4R variant should be taken into consideration for personalized treatment. In the future, a larger size cohort, accompanied with regular and longer follow-up, would be helpful.

The Mc4r gene is responsible for the development of experimentally induced testicular teratomas

Teratomas in mice, composed of different tissue types, are derived from primordial germ cells in the fetal gonads. Previously, we identified a locus responsible for experimental testicular teratoma (ETT) formation on chromosome 18, referred to as ett1. The strongest candidate sequence in the ett1 locus was found to be a missense mutation in the melanocortin 4 receptor (Mc4r), Mc4rG25S. We established a strain with a point mutation in the Mc4r gene in the ETT-nonsusceptible LT strain, called LT- Mc4rG25S, by genome editing. Surprisingly, highly developed ovarian teratomas (OTs), rather than testicular teratomas, appeared in the LT-Mc4rG25S strain. The results demonstrated that Mc4r is also one of the genes responsible for OT formation and suggested that missense mutations in Mc4r promote teratoma formation in both sexes. In this study, we performed ETT experiments in different host–graft combinations of the LT-Mc4rG25S and LT strains. Furthermore, the expression of MC4R in germ cells in the testis was demonstrated. Expression of Mc4r in testis was also confirmed by RT-PCR. The results demonstrated that MC4R is expressed in germ cells in the testis and that a point mutation in the Mc4r gene is responsible for ETT formation.

MC4R in Central and Peripheral Systems.

Obesity has emerged as a critical and urgent health burden during the current global pandemic. Among multiple genetic causes, melanocortin receptor-4 (MC4R), involved in food intake and energy metabolism regulation through various signaling pathways, has been reported to be the lead genetic factor in severe and early onset obesity and hyperphagia disorders. Most previous studies have illustrated the roles of MC4R signaling in energy intake versus expenditure in the central system, while some evidence indicates that MC4R is also expressed in peripheral systems, such as the gut and endocrine organs. However, its physiopathological function remains poorly defined. This review aims to depict the central and peripheral roles of MC4R in energy metabolism and endocrine hormone homeostasis, the diversity of phenotypes, biased downstream signaling caused by distinct MC4R mutations, and current drug development targeting the receptor.

Obesity and Mutations in Mc4r and Mc3r

Obesity and Mutations in Mc4r and Mc3r

Melanocortin-4 receptors activate sympathetic preganglionic neurons and elevate blood pressure via TRPV1.

Melanocortin-4 receptors (MC4Rs) expressed by the central nervous system are essential regulators of energy homeostasis, and Mc4r mutation is the most common cause of human monogenic obesity. Notably, patients with obesity carrying Mc4r mutations are protected against obesity-induced hypertension, and MC4R agonists elevate blood pressure (BP). Although increased sympathetic tone by MC4Rs is suggested to underlie this phenotype, the detailed mechanisms remain unclear. Here, we investigate how MC4Rs regulate the sympathetic preganglionic neurons and find that MC4Rs activate these neurons via the protein kinase A-dependent activation of the transient receptor potential vanilloid 1 (TRPV1) channel. Importantly, we demonstrate that the inhibition of TRPV1 prevents MC4R-induced elevation of BP but does not affect MC4R-induced anorexia. We further show that TRPV1 is responsible for MC4R-dependent activation of the sympathetic preganglionic neurons by high-fat diet. Together, our results provide insight into how MC4Rs regulate sympathetic function.

A rare form of ovotesticular difference of sex development (DSD) in combination with severe early-onset obesity due to MC4R mutation: clinical features and diagnostic challenges

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Potential of eight mutations for marker-assisted breeding in Chinese Lulai black pigs

Molecular marker-assisted selection (MAS) provides an efficient tool for pig breeding. In this study, according to the literature, we selected eight effective or causal mutations from eight functional genes, including five causal mutations in PHKG1 ( rs330928088), MUC13 ( rs319699771), IGF2 ( g.3072 G> A), VRTN ( g.20311_20312ins291), and MYH3 ( XM_013981330.2:g.-1805_-1810del) genes, and three effective mutations in LIPE ( rs328830166), LEPR ( rs45435518), and MC4R ( rs81219178) genes, to investigate their potential breeding effect in 418 Lulai pigs. The linear model was used to analyse the association between mutations and intramuscular fat (IMF) content, average backfat thickness, and muscle moisture %. The results revealed that amongst the three effective mutations, only the mutation in the LEPR gene, which affects IMF deposition, was significantly associated with IMF content. However, the other molecular markers were not significantly associated with the affected traits reported in previous studies, and these mutations are ineffective for MAS in the Lulai black pig population. Therefore, causal mutations in PHKG1, IGF2, and VRTN genes, and an effective mutation in LEPR gene could be used as effective breeding makers for MAS in Lulai pigs. These results can provide helpful information for further breeding in Lulai black pigs.

Robotic-Assisted Mini-Gastric By-Pass for Diabetes in Children: A First Case Report and Review of the Literature

Objectives: Obesity is one of the most common diseases of children across the globe with repercussion because of comorbidities like diabetes for the future followed by premature deaths. We aimed to report the world first case of robotic-assisted mini-gastric by-pass in 15 years old boy to treat diabetes and obesity. Surgical technique and review of the literature has been presented. Patient and Methods: Fifteen years old male with Body Mass Index (BMI) 58.6 at 125 percentile, and the patient was followed by dietetic counseling and with increasing metformin dosage treatment because of insulin resistance in his country. After 3 years of follow up the patient’s treatment was not successful and therefore the family addressed to our obesity council. Our genetic consultant assured the boy doesn’t have MC4R mutation. Other endocrinologic comorbidities was evaluated by a pediatrician specialist on obesity and referred to a pediatric endocrinologist. The Type 2 diabetes was diagnosed. Robotic assisted mini-gastric by-pass was planned. Under general anesthesia five instrument ports were placed. Then the robot was docked. The stomach was divided with stapler at the junction of the body and antrum, at a location where the jejunal loop can be brought up comfortably. The jejunal loop is brought up antecolic, and the stapler is used to anatomose the stomach and the small bowel at this point. The distal end of the gastric tube is anastomosed to the side of the small bowel. Methylene blue was given to ensure there was no leakage at the anastomosis and the stapling sites. The antidiabetics were stopped by the operation. The patient was followed for a month with a normalization of blood glucose levels and without medical nor surgical complication. Results: Operative time was 105 minutes. No intraoperative complication was encountered. The patient started walking 6 hours postoperatively. The first postoperative day glucose levels were within the normal limits. Oral contrast CT demonstrated neither leakage nor obstruction on the first day. Patient started oral intake within 24 hours and was discharged in 3 days without any postoperative complication. After 1 month of follow up we didn`t saw any perturbation on blood glucose level. Conclusion: Robotic-assisted mini gastric by-pass is feasible in diabetic children. The main postoperative advantages are early recovery, less pain and better cosmesis with a easily revisable and reversible operation.

Long-Term Weight Outcome After Bariatric Surgery in Patients with Melanocortin-4 Receptor Gene Variants: a Case–Control Study of 105 Patients

Pathogenic heterozygous MC4R variants are associated with hyperphagia and variable degrees of obesity. Several research groups have reported short-term weight loss outcomes after bariatric surgery in a few patients with MC4R variants, but lack of longer-term data prevents evidence-based clinical decision-making. Bariatric surgery patients with heterozygous (likely) pathogenic MC4R variants, from three collaborating centers in the Netherlands, France, and the UK, were compared to matched controls (matched 2:1 for age, sex, preoperative BMI, surgical procedure, and diabetes mellitus, but without MC4R mutations). Weight loss and regain outcomes up to 6years of follow-up were compared. At 60months of follow-up after RYGB, cases with MC4R variants showed weight regain with a mean of 12.8% (± 10.4 SD) total weight loss (TWL) from nadir, compared to 7.9% (± 10.5 SD) in the controls (p = 0.062). Among patients receiving SG, the cases with MC4R variants experienced inferior weight loss (22.6% TWL) during the first year of follow-up compared to the controls (29.9% TWL) (p = 0.010). This multicenter study reveals inferior mid-term weight outcomes of cases with MC4R variants after SG, compared to RYGB. Since adequate weight loss outcomes were observed after RYGB, this procedure would appear to be an appropriate surgical approach for this group. However, the pattern of weight regain seen in cases with MC4R variants after both RYGB and SG highlights the need for pro-active lifelong management to prevent relapse, as well as careful expectation management.

Functional Alterations of Two Novel MC4R Mutations Found in Argentinian Pediatric Patients with Early Onset Obesity

Functional Alterations of Two Novel MC4R Mutations Found in Argentinian Pediatric Patients with Early Onset Obesity

Link between MC4R mutations and adiposity.

Link between MC4R mutations and adiposity.

Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort.

Mutations in the melanocortin 4 receptor gene (MC4R) are associated with obesity but little is known about the prevalence and impact of such mutations throughout human growth and development. We examined the MC4R coding sequence in 5724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterised all non-synonymous MC4R variants and examined their association with anthropometric phenotypes from childhood to early adulthood. The frequency of heterozygous loss of function (LoF) mutations in MC4R was ~1/337 (0.30%), considerably higher than previous estimates. At age 18 years, mean differences in body weight, body mass index and fat mass between carriers and non-carriers of LoF mutations were 17.76kg (95% CI: 9.41, 26.10), 4.84kg/m2 (95% CI: 2.19, 7.49) and 14.78kg (95% CI: 8.56, 20.99), respectively. MC4R LoF mutations may be more common than previously reported and carriers of such variants may enter adult life with a substantial burden of excess adiposity.

Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity.

MC4R mutations represent the largest monogenic cause of obesity, resulting mainly from receptor misfolding and intracellular retention by the cellular quality control system. The present study aimed at determining whether pharmacological chaperones (PCs) that restore folding and plasma membrane trafficking by stabilizing near native protein conformation may represent valid therapeutic avenues for the treatment of melanocortin type 4 receptor–linked (MC4R-linked) obesity. To test the therapeutic PC potential, we engineered humanized MC4R (hMC4R) mouse models expressing either the WT human MC4R or a prevalent obesity-causing mutant (R165W). Administration of a PC able to rescue cell surface expression and functional activity of R165W-hMC4R in cells restored the anorexigenic response of the R165W-hMC4R obese mice to melanocortin agonist, providing a proof of principle for the therapeutic potential of MC4R-targeting PCs in vivo. Interestingly, the expression of the WT-hMC4R in mice revealed lower sensitivity of the human receptor to α–melanocyte-stimulating hormone (α-MSH) but not β-MSH or melanotan II, resulting in a lower penetrance obese phenotype in the WT-hMC4R versus R165W-hMC4R mice. In conclusion, we created 2 new obesity models, a hypomorphic highlighting species differences and an amorphic providing a preclinical model to test the therapeutic potential of PCs to treat MC4R-linked obesity.

Medicina de precisión en las obesidades infantiles

Obesity is currently one of the most common consultations in pediatrics due to its high prevalence rate in our environment. Even though an impaired balance between caloric intake and energy expenditure underlies the excessive accumulation of adipose tissue in most cases of childhood and adolescent obesity, there is a high interindividual variability in the susceptibility to develop obesity, which is based largely on each person’s singular genetic background. Advances in our understanding of the latter arise from the progressive unravelling of the pathophysiological bases of the mechanisms involved in the control of appetite, satiety, and energy expenditure. An important body of evidence in this field has derived from the study of an increasing number of cases of obesity with proven genetic (either syndromic or not), endocrinological or secondary etiology. Consequently, we now need to speak in term of «childhood obesities» when referring to the common phenotypic trait of excessive adipose tissue accumulation as the underlying pathophysiological bases are widely different between subjects; thus, individualized diagnostic and management approaches both, for obesity itself as for its associated comorbidities are required. Furthermore, the advances made in identifying patients with monogenic diseases cosegregating with the phenotype of obesity have considerably increased the modern pathophysiological bases of obesity. Therefore, it is imperative to individualize the diagnostic strategy, thus leading to a relevant change in the therapeutic approach. In fact, the results obtained by using the analog of melanocortin, setmelanotide, in patients with POMC (proopiomelanocortin), LEPR (leptin receptor) and PCSK1 (proprotein concertase subtilisin-kexin type 1) deficiency, and more recently studies of the structure and architecture of the MC4R (melanocortin receptor number 4), may allow a more precise analysis of the effects of the loss-of-function mutations in MC4R associated to obesity, as well as structural prediction of their responsiveness to setmelanotide, leading to a personalized therapy based on precision medicine.

SUN-LB107 Functional Characterisation of Human Heterozygous Non-Synonymous MC3R Variants

Background: Melanocortin 3 receptor (MC3R) is a member of the melanocortin family of G-protein coupled receptors predominantly expressed in hypothalamic tissue. Rodent models have implicated MC3R in the pathogenesis of obesity, however in humans the relationship between obesity phenotypes and impaired MC3R function is less well established than that observed for loss of function mutations in the homologous MC4R. Aim: Recently three heterozygous MC3R variants identified from candidate gene sequencing of an obese human cohort were reported to be pathogenic. We sought to functionally characterise the these MC3R non-synonymous variants (p.Q11X, p.I50T and p.A149V) in vitro and examine their associations to body mass index in an unselected population-based cohort. Methodology: Functional characterisation of each variant was undertaken in HEK293 cells transiently overexpressing either wild-type MC3R or the respective MC3R mutant where cAMP-dependant luciferase activity in response to alpha-melanocyte stimulating hormone (α-MSH) was measured. Body mass index (BMI) was compared between heterozygous carriers of the MC3R variants of interest and control participants (matched for age and sex and ethnicity) identified within the UK Biobank whole exome sequencing dataset. Results: Impairment of the canonical MC3R cAMP signalling response to α-MSH was observed for both p.Q11X and p.A149V MC3R variants when compared to wild-type MC3R receptor function in vitro. In contrast the cAMP signalling response of MC3R p.I50T to α-MSH was non-inferior to wild-type. Thirty-nine (male=18) heterozygous carriers of MC3R p.I50T were identified in the UK Biobank whole exome cohort. There was no statistical difference in median (IQR) BMI for female carriers 27.1(7.8) kg/m2 vs. matched female control participants 26.2(5.5) kg/m2 or male carriers 27.7(5.4) kg/m2 vs. matched male control participants 27.4(4.9) kg/m2. A single participant heterozygous for the MC3R p.Q11X variant (BMI= 28.3 kg/m2) and two participants heterozygous for MC3R p.A149V (BMI= 24.7 and 25.1 kg/m2 respectively) variant were identified in the UK Biobank whole exome cohort. BMI did not significantly differ from the match control population median for either of these variants. Conclusion: In vitro assessment and phenotype correlates suggest that MC3R p.I50T is not an obesity causing mutation. Despite evidence of impaired receptor function in vitro, MC3R p.Q11X and p.A149V did not associate with obesity in this unselected population and further study are required to elucidate their pathogenicity in humans.

Genetic Obesity and Bariatric Surgery Outcome in 1014 Patients with Morbid Obesity.

Mutations in the leptin-melanocortin pathway genes are known to cause monogenic obesity. The prevalence of these gene mutations and their effect on weight loss response after bariatric surgery are still largely unknown. To determine the prevalence of genetic obesity in a large bariatric cohort and evaluate their response to bariatric surgery. Mutation analysis of 52 obesity-associated genes. Patient inclusion criteria were a BMI > 50kg/m2, an indication for revisional surgery or an early onset of obesity (< 10years of age). A total of 1014 patients were included, of whom 30 (3%) were diagnosed with genetic obesity, caused by pathogenic heterozygous mutations in either MC4R, POMC, PCSK1, SIM1, or PTEN. The percentage total body weight loss (%TBWL) after Roux-en-Y gastric bypass (RYGB) surgery was not significantly different for patients with a mutation in MC4R, POMC, and PCSK1 compared with patients lacking a molecular diagnosis. Of the confirmed genetic obesity cases, only patients with MC4R mutations receiving a sleeve gastrectomy (SG) showed significantly lower %TBWL compared with patients lacking a molecular diagnosis, during 2years of follow-up. In this cohort of morbid obese bariatric patients, an estimated prevalence of monogenic obesity of 3% is reported. Among these patients, the clinical effects of heterozygous mutations in POMC and PCSK1 do not interfere with the effectiveness of most commonly performed bariatric procedures within the first 2years of follow-up. Patients with MC4R mutations achieved superior weight loss after primary RYGB compared with SG.

Screening of 31 genes involved in monogenic forms of obesity in 23 Pakistani probands with early-onset childhood obesity: a case report

BackgroundConsanguine families display a high degree of homozygosity which increases the risk of family members suffering from autosomal recessive disorders. Thus, homozygous mutations in monogenic obesity genes may be a more frequent cause of childhood obesity in a consanguineous population.MethodsWe identified 23 probands from 23 Pakistani families displaying autosomal recessive obesity. We have previously excluded mutations in MC4R, LEP and LEPR in all probands. Using a chip-based, target-region capture array, 31 genes involved in monogenic forms of obesity, were screened in all probands.ResultsWe identified 31 rare non-synonymous possibly pathogenic variants (28 missense and three nonsense) within the 31 selected genes. All variants were heterozygous, thus no homozygous pathogenic variants were found. Two of the rare heterozygous nonsense variants identified (p.R75X and p.R481X) were found in BBS9 within one proband, suggesting that obesity is caused by compound heterozygosity. Sequencing of the parents supported the compound heterozygous nature of obesity as each parent was carrying one of the variants. Subsequent clinical investigation strongly indicated that the proband had Bardet-Biedl syndrome.ConclusionsMutation screening in 31 genes among probands with severe early-onset obesity from Pakistani families did not reveal the presence of homozygous obesity causing variants. However, a compound heterozygote carrier of BBS9 mutations was identified, indicating that compound heterozygosity must not be overlooked when investigating the genetic etiology of severe childhood obesity in populations with a high degree of consanguinity.

271-OR: Whole-Exome Sequence Identifies Potentially Functional Rare Variants in Bardet-Biedl Syndrome (BBS) Genes that Associate with Obesity in American Indians

American Indians suffer from a high prevalence of obesity. Although their obesity is typically polygenic in nature, we are systematically analyzing known monogenic obesity genes in a population-based sample of Pima Indians. Previously, we have reported that 3% of this population carries functional mutations in MC4R. The goal of the current study is to determine whether variation in any of the 21 known BBS genes also contribute to obesity in this population. Analysis of whole exome sequence data from 6,809 Pima Indians (44.8% male; mean±SD age 34.8 ± 16.0 years; mean±SD maximum body mass index (BMI) 36.2 ± 8.8 kg/m2; 31.9% had T2D) identified 1,726 variants in the 21 BBS genes, of which 273 variants had a Combined Annotation Dependent Depletion (CADD) score &amp;gt;20 (top 1% most likely to be deleterious). Among these potentially deleterious variants, 32 were exclusive to, or enriched in, obese subjects (mean BMI for carriers &amp;gt;40). Five of the 32 variants were in the BBS9 gene and these were prioritized for functional studies. BBS mutations may impact obesity via leptin signaling, where BBS gene dysfunction has led to increased food intake. Therefore, in vitro luciferase reporter assays targeting STAT3 transcriptional activity were used to assess alterations in leptin signaling by the BBS variants. Analysis of a Thr549Ile (rs59252892) in BBS9 (mean BMI of Ile allele carriers was 41.3 ± 12.4 kg/m2 vs. 36.4 ± 8.8 kg/m2 for non-carriers, P=0.0008) showed that the Ile allele had a 28% increase in leptin signaling activity compared to the Thr allele (P=0.006, 5 experiments). Moreover, western blot analysis showed that the Ile allele had a 19% increase in STAT3 phosphorylation compared to the Thr allele. Comparable in vitro results were observed with a S545G, but not a K810E or L665F in BBS9. In summary, whole exome sequencing in Pima Indians has identified potentially functional variants in BBS9 that may increase risk for obesity through leptin signaling. Disclosure S.E. Day: None. Y.L. Muller: None. S. Kobes: None. H. Kim: Employee; Self; Regeneron Pharmaceuticals. C.V. Van Hout: Employee; Self; Regeneron Pharmaceuticals. N. Gosalia: Employee; Self; Regeneron Pharmaceuticals. B. Ye: Employee; Self; Regeneron Pharmaceuticals. A.R. Shuldiner: Employee; Self; Regeneron Pharmaceuticals. Stock/Shareholder; Self; Rhythm Pharmaceuticals, Inc. R.L. Hanson: None. C. Koroglu Altok: None. C. Bogardus: None. L.J. Baier: None.

OR12-3 Mice with MC4R Site Mutation (F51L) Develop Severe Obesity Independent of Gs-alpha/cAMP Signaling

The central melanocortin α-MSH acts through MC4R receptors, which are known to activate Gsα/cAMP signaling, to promote negative energy balance by inhibiting food intake (FI) and stimulating energy expenditure (EE). However, we have shown that mice with central Gsα deficiency become obese with decreased EE but without hyperphagia, and that MC4R inhibition of food intake in the paraventricular nucleus of the hypothalamus (PVN) is mediated via the G proteins Gqα/G11α. Previous in vitro studies have also shown that several MC4R mutations associated with early-onset human obesity, including F51L, have no effect on Gsα/cAMP signaling. To determine whether there are Gsα/cAMP-independent signaling pathways that regulate energy homeostasis through MC4Rs in vivo, we generated mice with an MC4R site mutation at F51L (MC4RF51L) using CRISPR/Cas9 and studied its metabolic consequences. MC4RF51L mice developed severe early-onset obesity with increased fat mass and body length, associated primarily with increased FI. In response to i.p. administered MC3R/MC4R agonist MTII, MC4RF51L mice showed impaired FI inhibition and EE stimulation. When MTII was directly administrated via a cannula unilaterally implanted into the PVN, FI was markedly inhibited in WT mice, but not in MC4RF51L mice, while heart rate was stimulated in both WT and MC4RF51L mice. In contrast, PVN administration of MTII did not affect EE in either WT or MC4RF51L mice. CREB phosphorylation levels in the PVN were similarly elevated in WT and MC4RF51L mice following i.p. injection of MTII, confirming that Gsα/cAMP signaling pathway is intact in these mutants. In addition, MC4RF51L mice had reduced glucose tolerance and insulin sensitivity secondary to obesity, as glucose intolerance was not seen in non-obese young mutants. MC4RF51L mice had normal body temperature at room temperature (22oC) and maintained their temperature when exposed to 6oC for 5 hours, consistent with an intact thermogenic response to acute cold conditions. Taken together, our data show that MC4R/Gsα/cAMP signaling in the PVN is not required for MTII-inhibited FI and that MC4R activation in the PVN has no observable effect on EE. Thus, these results show that additional MC4R pathways are required for normal energy homeostasis and provide support that MC4Rs mediate their actions on food intake in the PVN via G protein pathways other than Gsα, most likely Gqα/G11α. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases.

Characterization of Rare Variants in MC4R in African American and Latino Children With Severe Early-Onset Obesity.

Mutations in melanocortin receptor (MC4R) are the most common cause of monogenic obesity in children of European ancestry, but little is known about their prevalence in children from the minority populations in the United States. This study aims to identify the prevalence of MC4R mutations in children with severe early-onset obesity of African American or Latino ancestry. Participants were recruited from the weight management clinics at two hospitals and from the institutional biobank at a third hospital. Sequencing of the MC4R gene was performed by whole exome or Sanger sequencing. Functional testing was performed to establish the surface expression of the receptor and cAMP response to its cognate ligand α-melanocyte-stimulating hormone. Three hundred twelve children (1 to 18 years old, 50% girls) with body mass index (BMI) >120% of 95th percentile of Centers for Disease Control and Prevention 2000 growth charts at an age <6 years, with no known pathological cause of obesity, were enrolled. Eight rare MC4R mutations (2.6%) were identified in this study [R7S, F202L (n = 2), M215I, G252D, V253I, I269N, and F284I], three of which were not previously reported (G252D, F284I, and R7S). The pathogenicity of selected variants was confirmed by prior literature reports or functional testing. There was no significant difference in the BMI or height trajectories of children with or without MC4R mutations in this cohort. Although the prevalence of MC4R mutations in this cohort was similar to that reported for obese children of European ancestry, some of the variants were novel.