A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism

Challis, Benjamin; Pritchard, Lynn E.; Creemers, John W.M.; Delplanque, Jérôme; Keogh, Julia M.; Luan, Jian’an; Wareham, Nicholas J.; Yeo, Giles S.H.; Bhattacharyya, Sumit; Froguel, P.; White, Anne; Farooqi, I. Sadaf; O’Rahilly, Stephen

doi:10.1093/hmg/11.17.1997

Cited by 260 publications

(168 citation statements)

References 31 publications

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“…In addition, a patient with a compound heterozygous mutation in the PC1 gene that results in nonfunctional PC1 had severe childhood obesity (35). Similar obese conditions were found in a patient with a defect in POMC processing (36). As PC1 and PC2 are essential for the processing of a variety of proneuropeptides, alterations in the expression and protein biosynthesis of PC1 and PC2 are likely to have profound effects on neuropeptide homeostasis.…”

Section: Introductionmentioning

confidence: 81%

Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone

Sanchez¹,

Goldstein²,

Stuart³

et al. 2004

J. Clin. Invest.

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Regulation of energy balance by leptin involves regulation of several neuropeptides, including thyrotropinreleasing hormone (TRH).Synthesized from a larger inactive precursor, its maturation requires proteolytic cleavage by prohormone convertases 1 and 2 (PC1 and PC2). Since this maturation in response to leptin requires prohormone processing, we hypothesized that leptin might regulate hypothalamic PC1 and PC2 expression, ultimately leading to coordinated processing of prohormones into mature peptides. Using hypothalamic neurons, we found that leptin stimulated PC1 and PC2 mRNA and protein expression and also increased PC1 and PC2 promoter activities in transfected 293T cells. Starvation of rats, leading to low serum leptin levels, decreased PC1 and PC2 gene and protein expression in the paraventricular nucleus (PVN) of the hypothalamus. Exogenous administration of leptin to fasted animals restored PC1 levels in the median eminence (ME) and the PVN to approximately the level found in fed control animals. Consistent with this regulation of PCs in the PVN, concentrations of TRH in the PVN and ME were substantially reduced in the fasted animals relative to the fed animals, and leptin reversed this decrease. Further analysis showed that proteolytic cleavage of pro-thyrotropin-releasing hormone (proTRH) at known PC cleavage sites was reduced by fasting and increased in animals given leptin. Combined, these findings suggest that leptin-dependent stimulation of hypothalamic TRH expression involves both activation of trh transcription and stimulation of PC1 and PC2 expression, which lead to enhanced processing of proTRH into mature TRH.

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Section: Introductionmentioning

confidence: 81%

Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone

Sanchez¹,

Goldstein²,

Stuart³

et al. 2004

J. Clin. Invest.

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“…8,9 The majority of these mutations affect either the structure or function of a-and b-melanocyte-secreting hormone (MSH) or the cleavage from their precursor. 9,10,21,22 Two rare mutations in the N-terminal region of the POMC gene, likely affecting processing and sorting of POMC protein to the regulated secretory pathway, have also been associated with early-onset obesity. 11 In the present study, we describe a new mutation in the signal peptide of the POMC gene that inhibits the production and then the overall secretion of POMC protein.…”

Section: Discussionmentioning

confidence: 99%

A novel missense mutation in the signal peptide of the human POMC gene: a possible additional link between early-onset type 2 diabetes and obesity

et al. 2012

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Rare mutations in several genes have a critical role in the control of homeostatic mechanisms such as food-intake, energy balance and glucose metabolism. In this study, we performed a mutational screening in a 58-year-old woman presenting early-onset type 2 diabetes and central obesity. The entire coding regions of MC4R, MC3R, HNF1A, GCK and POMC (pro-opiomelanocortin) genes were analyzed by direct sequencing. A new missense mutation was identified within the POMC gene signal peptide sequence, resulting in a heterozygous substitution of an arginine for a glycine at codon 15 (p.A15G) that was excluded in 300 healthy normal weight controls. The mutation segregated in the family and was associated with overweight, type 2 diabetes, hypertension and coronary heart disease in the carriers. Functional studies demonstrated that POMC protein was not detectable in b-TC3 cells transfected with A15G-POMC vector as well as in their culture media, despite POMC mRNA levels were comparable for amount and stability to those of wild-type-transfected cells. In silico RNA folding prediction indicated that the mutation gives rise to a different RNA secondary structure, suggesting that it might affect translation and protein synthesis. To the best of our knowledge, this is the first report addressing the functional consequences of a mutation in the signal peptide of POMC. These findings further support the hypothesis that POMC-derived peptides might have a role in the control of peripheral glucose metabolism and suggest that disruption of central POMC secretion might represent an additional link between type 2 diabetes and obesity.

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“…With respect to nonsyndromic obesity, four mutation screening studies involving 601 nonsyndromic obese subjects have shown missense or nonsense mutations in just 7 individuals, implying that coding sequence variation in POMC is a very uncommon cause of nonsyndromic obesity (15)(16)(17)(18). Two genome-screening studies, in French obese sibling pairs and in Mexican-American ex- tended families, suggested strong evidence for linkage of plasma leptin levels to the region of chromosome 2 harboring the POMC gene (19,20).…”

Section: Discussionmentioning

confidence: 99%

Association Between Common Polymorphisms of the Proopiomelanocortin Gene and Body Fat Distribution

et al. 2005

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Rare mutations in the proopiomelanocortin (POMC) gene cause severe early-onset childhood obesity. However, it is unknown whether common variants in POMC are responsible for variation in body weight or fat distribution within the commonly observed range in the population. We tested for association between three polymorphisms spanning the POMC gene and obesity phenotypes in 1,428 members of 248 families. There was significant association between genotypes at the C8246T (P < 0.0001) and C1032G (P ‫؍‬ 0.003) polymorphisms and waist-to-hip ratio (WHR) corrected for age, sex, smoking, exercise, and alcohol consumption. Each T allele at C8246T (or G allele at C1032G) was associated with a 0.2-SD-higher WHR in a codominant fashion. When WHR was additionally corrected for BMI, thus providing a measure of body fat distribution throughout the range of BMI, there remained significant evidence for association with both markers that was of similar magnitude and statistical significance. There was no association between genotype at any polymorphism and BMI or plasma leptin level. These data show that genetic variants at the POMC locus influence body fat distribution within the normal range, suggesting a novel role for POMC in metabolic regulation. Diabetes 54: 2492-2496, 2005A bdominal obesity is a major risk factor for type 2 diabetes, coronary heart disease (CHD), colon cancer, and several other common and serious conditions. Although the definition of obesity typically relies on BMI, several studies suggest that, with respect to risk stratification, measurement of the waist-to-hip ratio (WHR) may be a superior predictor both of type 2 diabetes and CHD, possibly because of specific metabolic abnormalities accompanying central, rather than generalized, obesity (1,2). Both WHR and BMI are heritable traits, and various studies suggest that genes account for 25-70% of the observed variability (3,4).Melanocortin signaling in the hypothalamus plays a central role in the control of energy homeostasis. The proopiomelanocortin (POMC) gene is expressed in response to leptin signaling by neurons of the hypothalamic arcuate nucleus. Intracellular posttranslational processing of the POMC propeptide by prohormone convertase 2 leads to the production in these neurons of ␣-, ␤-, and ␥-melanocyte-stimulating hormones. These peptides signal to downstream target neurons in the lateral hypothalamus that express the melanocortin receptors MC3R and MC4R with resultant decrease in food intake and increase in energy expenditure (5). Rare mutations in the POMC gene cause monogenic, severe, early-onset obesity in humans; however, the influence of common polymorphisms in POMC on obesity phenotypes in less extreme individuals is unclear (6). POMC is also a precursor of adrenocorticotrophic hormone (ACTH); pathological ACTH excess results in severe central obesity. We have investigated the role of common polymorphisms of the POMC gene on abdominal obesity in a large family study. RESEARCH DESIGN AND METHODSSubject collection and phenotyping. The collect...

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A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism

Cited by 260 publications

References 31 publications

Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone

Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone

A novel missense mutation in the signal peptide of the human POMC gene: a possible additional link between early-onset type 2 diabetes and obesity

Association Between Common Polymorphisms of the Proopiomelanocortin Gene and Body Fat Distribution

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