Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: POMC
SNOMEDCT: 702949005;
Cytogenetic location: 2p23.3 Genomic coordinates (GRCh38): 2:25,160,860-25,168,580 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p23.3 | {Obesity, early-onset, susceptibility to} | 601665 | Autosomal dominant; Autosomal recessive; Multifactorial | 3 |
| Obesity, adrenal insufficiency, and red hair due to POMC deficiency | 609734 | Autosomal recessive | 3 |
The POMC gene encodes the preproopiomelanocortin (POMC) protein, which is sequentially cleaved to generate several active biopeptides, including adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH), and the opioid-receptor ligand beta-endorphin (summary by Krude et al., 1998).
Corticotropin (ACTH), synthesized by the anterior pituitary gland, stimulates the adrenal cortex. Human ACTH has a molecular weight of 4,541 and contains 39 amino acids (Lee et al., 1961). It has structural similarities to melanotropin (melanocyte-stimulating hormone; MSH). Human beta-melanotropin has 22 amino acid residues and a molecular weight of 2,661 (Harris, 1959). Work on the structure of the ACTH gene by restriction enzyme techniques showed that 6 hormones are derived from one gene: ACTH, lipotropin, alpha-MSH, beta-MSH, endorphin, and one other. Thus, extensive amino acid differences between these hormones were not adequate evidence for their being distinct. ACTH and beta-lipotropin (beta-LPH) are derived from a large precursor peptide. Each of these hormones is known to include smaller peptides having distinct biologic activities: alpha-melanotropin (alpha-MSH) and corticotropin-like intermediate lobe peptide (CLIP) are formed from ACTH; gamma-LPH and beta-endorphin are peptide components of beta-LPH. Beta-MSH is contained within gamma-LPH. The precursor peptide was called proopiomelanocortin (POMC) by Chretien et al. (1979).
Owerbach et al. (1981) assigned the POC gene to chromosome 2. From a study of a cell hybrid with a broken chromosome 2, Owerbach et al. (1981) found a suggestion that POC and ACP1 (171500) are closely linked in the distal portion of 2p. Using a polymorphism related to a POC probe in family studies, Cavalli-Sforza (1983) excluded linkage at a recombination fraction of 16% or less. By in situ hybridization combined with high resolution cytogenetics, Zabel et al. (1983) assigned the amylase gene to 1p21, the POMC gene to 2p23, and the somatostatin gene to 3q28. By fluorescence in situ hybridization, Satoh and Mori (1997) confirmed the assignment of POMC to 2p23 by Zabel et al. (1983) and refined the assignment to 2p23.3.
The POMC gene is polycistronic. Chang et al. (1980) determined the structural organization of the DNA segment containing POMC. No introns separate the various coding domains for ACTH, alpha-, beta-, and gamma-MSH (melanocyte-stimulating hormone), beta- and gamma-LPH, CLIP, and beta-endorphin. The glycosylated protein precursor (prohormone) from which ACTH and other hormones are derived has a molecular weight of 31,000 (Eipper and Mains, 1980). Glucocorticoids suppress ACTH release by inhibiting synthesis of the messenger RNA for the 31-kD prohormone.
In mouse follicular melanocytes, production of eumelanins and pheomelanins is under the control of 2 intercellular signaling molecules that exert opposite actions: alpha-MSH, which preferentially increases the synthesis of eumelanins, and agouti signal protein (ASP; 600201), whose expression favors the production of hair containing pheomelanins. Aberdam et al. (1998) reported that ASP not only affects mature melanocytes but can also inhibit the differentiation of melanoblasts. They showed that both alpha-MSH and forskolin promote the differentiation of murine melanoblasts into mature melanocytes, and that ASP inhibits this process. Expression of MITF (156845) and its binding to an M-box regulatory element is inhibited by ASP. Aberdam et al. (1998) also showed that in a murine melanoma cell line, ASP inhibits alpha-MSH-stimulated expression of tyrosinase (see 606933), tyrosinase-related protein-1 (TYRP1; 115501), and TYRP2 (191275) through an inhibition of the transcriptional activity of their respective promoters. Further, ASP inhibits alpha-MSH-induced expression of the MITF gene and reduces the level of MITF in the cells. Aberdam et al. (1998) concluded that ASP can regulate both melanoblast differentiation and melanogenesis, pointing out the key role of MITF in the control of these processes.
Ectopic secretion of ACTH may occur when the highly tissue-specific promoter of the human POMC gene is activated. This promoter is embedded within a defined CpG island, and CpG islands are usually considered to be unmethylated in all tissues. Newell-Price et al. (2001) demonstrated that much of this CpG island is methylated in normal nonexpressing tissues, in contrast to somatically expressed CpG island promoters previously reported, and is specially unmethylated in expressing tissues, tumors, and the POMC-expressing DMS-79 small-cell lung cancer cell line. A narrow 100-bp region is free of methylation in all tissues. The authors showed that these sites are methylated in normal nonexpressing tissues, which would prevent binding of E2F (189971), but are unmethylated in expressing tissue. They concluded that methylation in vitro is sufficient for silencing of expression, which is not reversed by treatment with trichostatin A, suggesting that inhibition of expression may be mediated by means other than recruitment of histone deacetylase activity.
Wardlaw (2001) reviewed the role of POMC in obesity. He noted that POMC is known as the precursor for pituitary ACTH, which is essential for maintaining adrenal cortical function. A well-recognized POMC deficiency syndrome is seen in patients with pituitary disease who fail to secrete ACTH normally and develop secondary adrenal insufficiency. These patients typically complain of anorexia and weight loss, which is corrected by glucocorticoid replacement. Several cases of genetic POMC deficiency had been described and, in contrast to the usual hypopituitary patient with selective pituitary POMC deficiency, these individuals have increased appetite and are obese. A similar obesity syndrome has been described in transgenic mice with targeted deletion of the coding region of the Pomc gene. These POMC-deficient patients and mice are obese despite having profound secondary adrenal insufficiency. Thus, the effects on energy homeostasis are quite different with generalized POMC deficiency as opposed to the typical hypopituitary patient with POMC deficiency limited to the pituitary. Wardlaw (2001) stated that POMC neurons in the hypothalamus are important regulators of energy homeostasis and that the POMC-derived peptide alpha melanocyte-stimulating hormone (alpha-MSH) and brain melanocortin receptors play a key role in this process.
In normal-weight humans, Fehm et al. (2001) examined the effects of a 6-week daily treatment with the melanocortin-4 receptor (MC4R; 155541) agonists MSH/ACTH(4-10) and desacetyl alpha-MSH on body weight, body fat, and plasma concentrations of leptin (164160) and insulin (176730). Data indicated a reducing effect of MSH/ACTH(4-10) on body adiposity within this treatment period. The authors concluded that these findings confirm and extend to the human the findings of animal models indicating an essential role of the hypothalamic melanocortin system in body weight control.
To determine whether d-FEN (D-fenfluramine) activates POMC neurons, Heisler et al. (2002) performed dual-labeling immunohistochemical experiments using antisera to alpha-melanocyte-stimulating hormone. Threshold anorexic doses of d-FEN significantly and consistently induced FOS-like immunoreactivity in alpha-melanocyte-stimulating hormone immunoreactive neurons throughout the arcuate nucleus of the hypothalamus. A similar pattern of d-FEN-induced FOS-like immunoreactivity was observed in arcuate nucleus cells expressing POMC mRNA. Heisler et al. (2002) concluded that these data strongly suggest that threshold anorexic doses of d-FEN activate POMC neurons in the arcuate nucleus. Heisler et al. (2002) demonstrated that d-FEN directly activates POMC neurons, in which 5-HT (5-hydroxytryptamine; serotonin) receptors are expressed, and that action at 5-HT receptors mediates a component of the anorexic effect of d-FEN.
The POMC gene is occasionally expressed in nonpituitary tumors leading to Cushing disease (see 219090). Bronchial carcinoid tumors, one of the most frequent sources for ectopic ACTH secretion, often display numerous features of the corticotroph phenotype. To identify new markers of corticotroph differentiation in these tumors, Pascual-Le Tallec et al. (2002) compared the pattern of POMC expression in ACTH-secreting (ACTH+) and nonsecreting (ACTH-) bronchial carcinoids by differential display/RT-PCR. In ACTH+ tumors, beside the expected POMC gene, they identified cFos and KIAA1775, a large expressed sequence tag encoding a putative protocadherin-related protein. On the other hand, the tetraspanin TM4SF5 gene (604657) was specifically expressed in ACTH- tumors. The authors concluded that corticotroph differentiation of bronchial carcinoid tumors is accompanied by induction and repression of specific genes.
In cellular studies, Bilodeau et al. (2006) demonstrated that BRG1 (603254) was essential for glucocorticoid-induced transrepression of the POMC gene in the negative feedback regulation mechanism. BRG1 was required to stabilize interactions between the glucocorticoid receptor (GCCR; 138040) and NGFIB (139139) or HDAC2 (605164). In 17 (47%) of 36 human corticotroph adenomas, which are found in Cushing disease and associated with glucocorticoid resistance, Bilodeau et al. (2006) found altered expression and/or subcellular localization of either BRG1 (12 tumors) or HDAC2 (5 tumors) compared to adjacent normal pituitary tissue.
Using reporter gene, gel shift, and immunoprecipitation assays in rodent cells, Kitamura et al. (2006) demonstrated that Foxo1a and Stat3 (102582) exerted opposing actions on the expression of Agrp and Pomc through transcriptional interference. Foxo1a promoted opposite patterns of coactivator-corepressor exchange at the Pomc and Agrp promoters, resulting in activation of Agrp and inhibition of Pomc.
Parton et al. (2007) disrupted glucose sensing in glucose-excited POMC neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene, 600937) that prevents ATP-mediated closure of potassium-ATP channels. They showed that this genetic manipulation impaired the whole body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiologic control of blood glucose. Parton et al. (2007) also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes (see 125853). The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein-2 (UCP2; 601693), a mitochondrial protein that impairs glucose-stimulated production. UCP2 negatively regulates glucose sensing in POMC neurons. They authors found that genetic deletion of UCP2 prevented obesity-induced loss of glucose sensing, and that acute pharmacologic inhibition of UCP2 reverses loss of glucose sensing. Parton et al. (2007) concluded that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes.
By using a combination of pharmacologic, molecular genetic, electrophysiologic, and feeding studies, Mineur et al. (2011) found that activation of hypothalamic alpha-3 (118503)-beta-4 (118509) nicotinic acetylcholine receptors leads to activation of POMC neurons. POMC neurons and subsequent activation of melanocortin-4 receptors (MC4R; 155541) were critical for nicotinic-induced decreases in food intake in mice. The study of Mineur et al. (2011) demonstrated that nicotine decreases food intake and body weight by influencing the hypothalamic melanocortin system and identified critical molecular and synaptic mechanisms involved in nicotine-induced decreases in appetite.
Koch et al. (2015) tested whether cannabinoid receptor-1 (CB1R; 114610)-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. They showed that chemical promotion of CB1R activity increases feeding, and, notably, CB1R activation also promoted neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, since 'designer receptors exclusively activated by designer drugs' (DREADD)-mediated inhibition of POMC neurons diminished CB1R-driven feeding, whereas DREADD-mediated activation of POMC neurons enhanced it. The POMC gene encodes both the anorexigenic peptide alpha-MSH and the opioid peptide beta-endorphin. CB1R activation selectively increases beta-endorphin but not alpha-MSH release in hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Koch et al. (2015) concluded that these results uncovered a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.
Early-onset Obesity, Adrenal Insufficiency, and Red Hair
In 2 unrelated children with early-onset obesity, adrenal insufficiency, and red hair (OBAIRH; 609734), Krude et al. (1998) identified biallelic loss-of-function mutations in the POMC gene. One patient was compound heterozygous for 2 mutations in exon 3 (176830.0001 and 176830.0002) that interfered with appropriate synthesis of ACTH and alpha-MSH. The other patient was homozygous for a mutation in exon 2 (176830.0003) that abolished POMC translation. The findings represented the first examples of a genetic defect of the POMC gene and defined a new monogenic endocrine disorder consisting of early-onset obesity, adrenal insufficiency, and red hair pigmentation. The POMC gene was chosen for study because studies in animal models had elucidated a central role of alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4 receptor. Comuzzie et al. (1997) had identified a major quantitative trait locus (601694) determining serum leptin levels and fat mass located on 2p21, in close proximity to the POMC locus. These findings led to the proposal of an association of POMC with human obesity. The dual role of alpha-MSH in regulating food intake (Fan et al., 1997) and the identification of mutant alleles at the MSH receptor locus (MC1R; 155555) producing hair pigmentation phenotypes (Robbins et al., 1993) predicted that the phenotype associated with a defect in POMC function would include obesity and alteration in pigmentation, in addition to ACTH deficiency.
In 3 children with early-onset obesity, red hair, and secondary hypocortisolism, Krude et al. (2003) identified homozygosity or compound heterozygosity for mutations in the POMC gene (see 176830.0003-176830.0007).
In an 18-year-old woman, born of consanguineous parents of North African descent, with OBAIRH, Clement et al. (2008) identified a homozygous frameshift mutation in the POMC gene (176830.0008). The mutation, which was found by direct sequencing based on the clinical presentation of the patient, segregated with the disorder in the family and was not found in 363 aged-matched controls in France. Functional studies of the variant were not performed, but the patient had undetectable levels of plasma cortisol, ACTH, and lipotropin hormone.
Associations Pending Confirmation
Feder et al. (1985) used 2 approaches to test the possible implication of the POMC gene in schizophrenia (181500) and bipolar affective illness. Both yielded negative results. The first method involved testing normals and patients with a variety of restriction enzymes to detect a difference due to a single nucleotide substitution that is directly responsible for the disease state. The second approach, using linkage disequilibrium, made use of DNA polymorphisms so close to the POMC gene that association would be found if a POMC mutation were responsible for all or many of the cases of either psychiatric disease. The use of the DNA markers for linkage in specific pedigrees is limited by the low penetrance and uncertain mode of inheritance. Lacaze-Masmonteil et al. (1987) studied POMC transcripts of human nonpituitary tissues.
Hinney et al. (1998) screened the coding region of the POMC gene in 96 extremely obese children and adolescents, 60 healthy underweight individuals, and 46 patients with anorexia nervosa. The authors identified a total of 10 variants, none of which were identical to any of the 3 mutations described by Krude et al. (1998). Hinney et al. (1998) concluded that the POMC gene harbors several different polymorphisms and mutations, none of which could readily be associated with the phenotypes under study.
Baker et al. (2005) tested for association between 3 SNPs in the noncoding region of the POMC gene and obesity phenotypes in 1,428 members of 248 families originally ascertained for essential hypertension. There was significant association between genotypes at 8246C-T (rs1042571) in the 3-prime UTR and 1032C-G (rs1009388) in intron 1 and waist-to-hip ratio (WHR) corrected for age, sex, smoking, exercise, alcohol consumption, and BMI: each T or G allele was associated with a 0.2 standard deviation-higher WHR in a codominant fashion. There was no association between POMC genotype and BMI or plasma leptin level. Baker et al. (2005) concluded that genetic variants at the POMC locus influence body fat distribution.
To examine the contribution of the POMC gene in the variability of serum insulin levels in obese children, Santoro et al. (2004) performed an association study using a 9-bp insertional polymorphism, AGC AGC GGC, between nucleotides 6979 and 6998 of the POMC gene (Echwald et al., 1999; Miraglia del Giudice et al., 2001). This polymorphism causes the insertion of 3 amino acids, ser ser gly, between codons 94 and 100 in the region of the 16-kD fragment C-terminal to gamma-MSH. In 380 Italian obese children and adolescents (185 girls), allelic frequencies were comparable in patients (0.053) and in 300 lean controls of Mediterranean descent (0.045). Santoro et al. (2004) showed that this polymorphism in obese patients was associated with differences in fasting insulin levels; this finding persisted after correction for age, sex, and pubertal stage. Heterozygotes had 24% higher mean insulin levels than those homozygous for the wildtype allele and showed a stronger correlation between insulin and body mass index (P less than 0.001).
Yaswen et al. (1999) generated POMC-null mice that developed obesity and had defective adrenal development and altered pigmentation. When treated with a stable alpha-MSH agonist, mutant mice lost more than 40% of their excess weight after 2 weeks. Yaswen et al. (1999) concluded that POMC-null mice provide a model for studying human POMC deficiency.
To test the hypothesis that leptin selectively activates POMC neurons, Cowley et al. (2001) generated a strain of transgenic mice expressing green fluorescent protein under the transcriptional control of mouse Pomc genomic sequences, including a region that is required for accurate neuronal expression. Cowley et al. (2001) made electrophysiologic recordings on POMC neurons, and showed that leptin increases the frequency of action potentials in the anorexigenic POMC neurons by 2 mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide Y (NPY; 162640)/GABA neurons. Furthermore, Cowley et al. (2001) showed that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of their results, Cowley et al. (2001) proposed an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus. In their model, leptin directly depolarizes the POMC neurons while simultaneously hyperpolarizing the somata of NPY-GABA neurons, and diminishes release from NPY/GABA terminals. This diminished GABA release disinhibits the POMC neurons. Together, the direct and indirect effects of leptin result in an activation of POMC neurons and an increased frequency of action potentials.
Balthasar et al. (2004) generated mice with conditional deletion of leptin receptors (see 601007) on POMC neurons and observed mild obesity, hyperleptinemia, and altered expression of hypothalamic neuropeptides. Because the body weight increase was only 18% of that seen in mice with complete deficiency of leptin receptors, the authors concluded that leptin receptors on POMC neurons are required but not solely responsible for leptin's regulation of body weight homeostasis.
Gao et al. (2007) administered estradiol (E2) to wildtype mice and rats and observed a robust increase in the number of excitatory inputs to POMC neurons in the arcuate nucleus. The rearrangement of synapses was leptin independent, as it was also observed in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice, and was paralleled by decreased food intake and body weight gain, as well as increased energy expenditure. Chronic E2 administration in a brain-specific Stat3-knockout mouse model, a phenotype that closely resembles that of ob/ob and db/db mice, had no effect on body weight, demonstrating that the estrogen-induced decrease in body weight was dependent on Stat3 activation in the brain. Gao et al. (2007) concluded that synaptic plasticity of arcuate nucleus feeding circuits is an inherent element in body weight regulation.
Padilla et al. (2010) used BrdU labeling of mouse embryos in utero to show that Pomc was first expressed in neuronal cells in the hypothalamic ventricular zone at embryonic day (E) 10.5-E11.5. Expression of NPY first appeared in laterally situated cells at E13.5, with subsequent expression in the ventromedial arcuate nucleus of the hypothalamus (ARH). Some cells showed coexpression of these genes at midgestation, whereas adult cell populations showed mutually exclusive expression. Further studies indicated that about half of embryonic Pomc-expressing precursors subsequently adopted a non-Pomc fate in adult mice, and that nearly one-quarter of the mature Npy-positive cells shared a common progenitor with Pomc-positive cells. These findings were consistent with the hypothesis that cell fate decisions may be influenced by factors during gestation. Importantly, the 2 best-characterized ARH populations, neurons that express orexigenic NPY and neurons that express anorexigenic POMC, produce antagonistic effects on food intake and energy homeostasis, which may have implications for body weight and obesity.
In Labrador Retriever dogs, Raffan et al. (2016) found that increased body weight, adiposity, and food-seeking behavior was associated with a 14-bp frameshift deletion in the Pomc gene. The variant was found by sequencing of candidate genes involved in the hypothalamic leptin melanocortin signaling pathway. The variant was initially found in 10 of 15 obese dogs (2 homozygous and 8 heterozygous), and in 2 of 18 lean dogs (both heterozygous), with a subsequent similar association found in 310 additional Labrador retrievers. In addition, there was a higher frequency of the Pomc deletion allele in 'assistance' dogs than in pets, and Raffan et al. (2016) noted that assistance dogs are often trained using food rewards. The same variant was also associated with increased body size and food motivation in flat-coat retrievers, but was not found in 38 other diverse breeds. There was an additive effect, with heterozygous dogs showing an intermediate phenotype. The frameshift variant was predicted to disrupt the production of the neuroactive peptides beta-MSH (beta-melanocyte-stimulating hormone) and beta-endorphin, which are believed to regulate appetite and body weight. Functional studies of the variant and studies of cells from carrier dogs were not performed.
Mankowska et al. (2017) confirmed the findings of Raffan et al. (2016) in Labrador retriever dogs in Poland. The variant was associated with increased body weight, but not with a 5-point body condition score. In contrast to the findings of Raffan et al. (2016), Mankowska et al. (2017) found only a statistically significant difference in weight between control dogs and dogs who were homozygous for the allele but not dogs heterozygous for the allele, suggesting that the allele presents a recessive effect. The variant was present at a low frequency (0.17) in Labrador retrievers and was not found in golden retrievers, beagles, or cocker spaniels. Functional studies of the variant and studies of cells from carrier dogs were not performed.
Among 57 Labrador retrievers with diabetes mellitus and 61 nondiabetic Labrador retrievers, Davison et al. (2017) found no association between the 14-bp deletion in exon 3 of the Pomc gene and the presence of diabetes.
In a 3-year-old German girl with early-onset obesity, adrenal insufficiency due to ACTH deficiency, and red hair (OBAIRH; 609734), Krude et al. (1998) identified compound heterozygosity for 2 mutations in exon 3 of the POMC gene. A 7013G-T transversion in the paternal allele resulted in a glu79-to-ter (G79X) substitution. Truncation of the POMC protein at codon 79 predicted complete absence of ACTH, alpha-MSH, and beta-endorphin, encoded further downstream. On the maternal allele, a 1-bp deletion at nucleotide 7133 caused a frameshift predicted to disrupt the structure of the receptor-binding core motif of ACTH and alpha-MSH and introduced a premature termination at codon 131 (176830.0002). Compound heterozygosity for these 2 mutations was found not only in the proband, the second-born daughter of the family, but also in the first-born son who died at 7 months of age of hepatic failure following severe cholestasis, which in the postmortem examination was found to be caused by adrenal insufficiency due to bilateral adrenal hypoplasia. Mutation analysis in the son was performed using a stored newborn-screening filter-paper blood specimen.
For discussion of the 1-bp deletion (7133delC) in the POMC gene that was found in compound heterozygous state in a patient with early-onset obesity, adrenal insufficiency, and red hair (OBAIRH; 609734) by Krude et al. (1998), see 176830.0001.
In a 5-year-old German boy with early-onset obesity, adrenal insufficiency, and red hair (OBAIRH; 609734), Krude et al. (1998) found homozygosity for a 3804C-A transversion in exon 2 of the POMC gene, resulting in an additional 5-prime start codon, which abolished POMC translation. The patient was a boy with transient neonatal hypoglycemia. Birth weight was normal, but obesity was first noted at the age of 5 months. After a febrile seizure, blood glucose measurement showed hypoglycemia and hyponatremia leading to an endocrinologic investigation which showed complete ACTH deficiency. With hydrocortisone substitution, the boy's subsequent development was uneventful apart from abnormal eating behavior causing progressive obesity. His intellectual and emotional assessments yielded normal results. As in the other patient (176830.0001), MRI revealed normal pituitary morphology.
In a Dutch boy with POMC, Krude et al. (2003) identified homozygosity for the 3804C-A transversion in the POMC gene. His parents were heterozygous for the mutation, and his brother carried only the wildtype allele. In this patient, the hair color changed to brown in the second to third years of life. Krude et al. (2003) noted that carriers of this mutation are from a circumscribed geographical area in Europe (the Netherlands, Switzerland, and Germany), suggesting a founder effect.
Challis et al. (2002) sequenced the POMC coding region in 262 Caucasian subjects with a history of severe obesity from childhood (see 601665). Two children were found to be heterozygous for an arg236-to-gly (R236G) missense mutation, which is predicted to disrupt the dibasic cleavage site between beta-melanocyte-stimulating hormone (beta-MSH) and beta-endorphin. Beta-TC3 cells transfected with the mutant POMC cDNA produced a mutant beta-MSH/beta-endorphin fusion protein. This fusion protein bound to the human melanocortin-4 receptor (MC4R) with an affinity similar to its natural ligands, but had a markedly reduced ability to activate the receptor. This variant cosegregated with early-onset obesity in the 3-generation family of 1 of the children and was absent in 412 normal weight Caucasian controls. Combining results from 5 studies, mutations disrupting this processing site were present in 0.88% of subjects with early-onset obesity and 0.22% of normal weight controls. The authors suggested that the R236G mutation may confer an inherited susceptibility to obesity through the production of an aberrant fusion protein that has the capacity to interfere with central melanocortin signaling.
In a Swiss girl with early-onset obesity, adrenal insufficiency, and red hair (OBAIRH; 609734), Krude et al. (2003) identified compound heterozygous mutations in the POMC gene: a 2-bp insertion (7100insGG) in exon 3, and a 3804C-A transversion (176830.0003) in exon 2. Her father and mother were heterozygous for the mutations, respectively; her brother also carried the 3804C-A transversion. The patient's hair color changed from red to brown in the second to third years of life.
In a Slovenian boy with early-onset obesity, adrenal insufficiency, and red hair (OBAIRH; 609734), Krude et al. (2003) identified compound heterozygosity for mutations in exon 3 of the POMC gene: a 6851A-T transversion, resulting in a lys25-to-ter (L25X) substitution, and a 1-bp deletion at nucleotide 6996 (176830.0007). His father and mother were heterozygous for the mutations, respectively.
For discussion of the 1-bp deletion (6996del) in the POMC gene that was found in compound heterozygous state in a patient with early-onset obesity, adrenal insufficiency, and red hair (OBAIRH; 609734) by Krude et al. (2003), see 176830.0006.
In an 18-year-old woman, born of consanguineous parents of North African descent, with early-onset obesity, adrenal insufficiency, and red hair (OBAIRH; 609734), Clement et al. (2008) identified a homozygous 1-bp insertion (c.6922insC) in the POMC gene. The mutation was predicted to result in a frameshift and premature termination, eliminating the alpha-MSH domain and preventing the production of any normal POMC-derived peptides. The mutation, which was found by direct sequencing based on the clinical presentation of the patient, segregated with the disorder in the family and was not found in 363 aged-matched controls in France. Functional studies of the variant were not performed, but the patient had undetectable levels of plasma cortisol, ACTH, and lipotropin hormone.
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