Expression, candidate gene, and population studies of the melanocortin 5 receptor.

In mouse the melanocortin 5 receptor is known to regulate sebaceous gland function. To clarify its role in man, we have studied melanocortin 5 receptor expression in skin, and allelic variation at the melanocortin 5 receptor locus in diverse human populations and candidate disease groups. Melanocortin 5 receptor protein and mRNA expression were studied by immunohistochemistry and reverse transcriptase polymerase chain reaction. Melanocortin 5 receptor mRNA was detected in normal skin and cultured keratinocytes but not in cultured fibroblasts or melanocytes. Immunohistochemistry revealed melanocortin 5 receptor immunoreactivity in the epithelium and appendages, including the sebaceous gland, eccrine glands, and apocrine glands, as well as low level expression in the interfollciular epidermis. In order to screen for genetic diversity in the melanocortin 5 receptor that might be useful for allelic association studies we sequenced the entire melanocortin 5 receptor coding region in a range of human populations. One nonsynonymous change (Phe209Leu) and four synonymous changes (Ala81Ala, Asp108Asp, Ser125Ser, and Thr248Thr) were identified. Similar results were found in each of the populations except for the Inuit in which only the Asp108Asp variant was seen. The apparent "global distribution" of melanocortin 5 receptor variants may indicate that they are old in evolutionary terms. Variation of melanocortin 5 receptor was examined in patients with acne (n = 21), hidradenitis supprativa (n = 4), and sebaceous gland lesions comprising sebaceous nevi, adenomas, and hyperplasia (n = 13). No additional mutations were found. In order to determine the functional status of the Phe209Leu change, increase in cAMP in response to stimulation with alpha-melanocyte-stimulating hormone was measured in HEK-293 cells transfected with either wild-type or the Phe209Leu variant. The variant melanocortin 5 receptor was shown to act in a concentration-dependent manner, which did not differ from that of wild type. We have therefore found no evidence of a causative role for melanocortin 5 receptor in sebaceous gland dysfunction, and in the absence of any association between variation at the locus and disease group, the pathophysiologic role of the melanocortin 5 receptor in man requires further study.

[1]  J. Rees,et al.  The melanocortin 1 receptor (MC1R): more than just red hair. , 2000, Pigment cell research.

[2]  I. Jackson,et al.  Evidence for variable selective pressures at MC1R. , 2000, American journal of human genetics.

[3]  N. Flanagan,et al.  Genetic Studies of the Human Melanocortin‐1 Receptor , 1999, Annals of the New York Academy of Sciences.

[4]  L. Yaswen,et al.  Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin , 1999, Nature Medicine.

[5]  J. Wikberg,et al.  Loss of function mutations of the human melanocortin 1 receptor are common and are associated with red hair. , 1999, Biochemical and biophysical research communications.

[6]  R. Adan,et al.  Melanocortins and cardiovascular regulation. , 1998, European journal of pharmacology.

[7]  I. Jackson,et al.  Melanocortin receptors and antagonists regulate pigmentation and body weight. , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[8]  J. Wikberg,et al.  Chimeric melanocortin MC1 and MC3 receptors: identification of domains participating in binding of melanocyte-stimulating hormone peptides. , 1998, Molecular pharmacology.

[9]  A. Grüters,et al.  Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans , 1998, Nature Genetics.

[10]  J. Burbach,et al.  Expression of melanocortin-5 receptor in secretory epithelia supports a functional role in exocrine and endocrine glands. , 1998, Endocrinology.

[11]  J. Wikberg,et al.  Evidence indicating that the extracellular loops of the mouse MC5 receptor do not participate in ligand binding , 1998, Molecular and Cellular Endocrinology.

[12]  Ximena Opitz-Araya,et al.  Exocrine Gland Dysfunction in MC5-R-Deficient Mice: Evidence for Coordinated Regulation of Exocrine Gland Function by Melanocortin Peptides , 1997, Cell.

[13]  P. Frändberg,et al.  Glutamine235 and arginine272 in human melanocortin 5 receptor determines its low affinity to MSH. , 1997, Biochemical and biophysical research communications.

[14]  H. Schiöth,et al.  Deletions of the N‐terminal regions of the human melanocortin receptors , 1997, FEBS letters.

[15]  P. Prusis,et al.  Characterisation of D117A and H260A mutations in the melanocortin 1 receptor , 1997, Molecular and Cellular Endocrinology.

[16]  J. Wikberg,et al.  Characterisation of the melanocortin 4 receptor by radioligand binding. , 1996, Pharmacology & toxicology.

[17]  Y. Konda,et al.  Molecular cloning, expression, and characterization of a fifth melanocortin receptor. , 1994, Biochemical and biophysical research communications.

[18]  P. Sokoloff,et al.  Molecular cloning and characterization of the rat fifth melanocortin receptor. , 1994, Biochemical and biophysical research communications.

[19]  M. Parmentier,et al.  Molecular cloning of a mouse melanocortin 5 receptor gene widely expressed in peripheral tissues. , 1994, Biochemistry.

[20]  J. Wikberg,et al.  Molecular cloning of a novel human melanocortin receptor. , 1993, Biochemical and biophysical research communications.

[21]  S. Watson,et al.  Molecular cloning of a novel melanocortin receptor. , 1993, The Journal of biological chemistry.

[22]  J. Wikberg,et al.  Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA , 1992, FEBS letters.

[23]  M. Mortrud,et al.  The cloning of a family of genes that encode the melanocortin receptors. , 1992, Science.

[24]  S. Shuster,et al.  Control and function of sebaceous glands. , 1989, Physiological reviews.

[25]  J. B. Tatro,et al.  Specific receptors for alpha-melanocyte-stimulating hormone are widely distributed in tissues of rodents. , 1987, Endocrinology.

[26]  V. Randall,et al.  The synergistic action of alpha-melanocyte-stimulating hormone and testosterone of the sebaceous, prostate, preputial, Harderian and lachrymal glands, seminal vesicles and brown adipose tissue in the hypophysectomized-castrated rat. , 1975, The Journal of endocrinology.

[27]  D. I. Våge,et al.  The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. , 1996, Recent progress in hormone research.