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

In mouse the melanocortin 5 receptor is known to regulate sebaceous gland f unction. To clarify its role in man, we have studied melanocortin 5 recepto r expression in skin, and allelic variation at the melanocortin 5 receptor locus in diverse human populations and candidate disease groups. Melanocort in 5 receptor protein and mRNA expression were studied by immunohistochemis try and reverse transcriptase polymerase chain reaction. Melanocortin 5 rec eptor mRNA was detected in normal skin and cultured keratinocytes but not i n cultured fibroblasts or melanocytes, Immunohistochemistry revealed melano cortin 5 receptor immunoreactivity in the epithelium and appendages, includ ing the sebaceous gland, eccrine glands, and apocrine glands, as well as lo w 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 (P he209Leu) and four synonymous changes (Ala81Ala, Asp108Asp, Ser125Ser, and Thr248Thr) were identified. Similar results were found in each of the popul ations except for the Inuit in which only the Asp108Asp variant was seen. T he apparent "global distribution" of melanocortin 5 receptor variants may i ndicate that they are old in evolutionary terms. Variation of melanocortin 5 receptor was examined in patients with acne (n = 21), hidradenitis suppra tiva (n = 4), and sebaceous gland lesions comprising sebaceous nevi, adenom as, and hyperplasia (n = 13). No additional mutations were found, In order to determine the functional status of the Phe209Leu change, increase in cAM P in response to stimulation with a-melanocyte-stimulating hormone was meas ured in HEK-293 cells transfected with either wildtype or the Phe209Leu var iant. The variant melanocortin 5 receptor was shown to act in a concentrati on-dependent manner, which did not differ from that of wild type. We have t herefore found no evidence of a causative role for melanocortin 5 receptor in sebaceous gland dysfunction, and in the absence of any association betwe en variation at the locus and disease group, the pathophysiologic role of t he melanocortin 5 receptor in man requires further study.