Hatta N, Dixon C, Ray A J, Phillips S R, Cunliffe W J, Dale M, Todd C, Meggit S, Birch-MacHin M A, Rees J L
Department of Dermatology, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.
J Invest Dermatol. 2001 Apr;116(4):564-70. doi: 10.1046/j.0022-202x.2001.01286.x.
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.
在小鼠中，已知黑皮质素5受体可调节皮脂腺功能。为阐明其在人类中的作用，我们研究了黑皮质素5受体在皮肤中的表达，以及不同人群和候选疾病组中黑皮质素5受体基因座的等位基因变异。通过免疫组织化学和逆转录聚合酶链反应研究了黑皮质素5受体蛋白和mRNA的表达。在正常皮肤和培养的角质形成细胞中检测到黑皮质素5受体mRNA，但在培养的成纤维细胞或黑素细胞中未检测到。免疫组织化学显示黑皮质素5受体在上皮和附属器中具有免疫反应性，包括皮脂腺、小汗腺和大汗腺，以及在毛囊间表皮中的低水平表达。为了筛选黑皮质素5受体中可能对等位基因关联研究有用的遗传多样性，我们对一系列人群的整个黑皮质素5受体编码区进行了测序。鉴定出一个非同义变化（Phe209Leu）和四个同义变化（Ala81Ala、Asp108Asp、Ser125Ser和Thr248Thr）。除因纽特人外，在其他人群中均发现了类似结果，因纽特人中仅观察到Asp108Asp变体。黑皮质素5受体变体的明显“全球分布”可能表明它们在进化上较为古老。对痤疮患者（n = 21）、化脓性汗腺炎患者（n = 4）以及包括皮脂腺痣、腺瘤和增生在内的皮脂腺病变患者（n = 13）的黑皮质素5受体变异进行了检测。未发现其他突变。为了确定Phe209Leu变化的功能状态，在转染了野生型或Phe209Leu变体的HEK - 293细胞中测量了α - 黑素细胞刺激素刺激后cAMP的增加。结果显示变体黑皮质素5受体以浓度依赖方式起作用，与野生型无差异。因此，我们没有发现黑皮质素5受体在皮脂腺功能障碍中起致病作用的证据，并且由于该基因座的变异与疾病组之间没有任何关联，黑皮质素5受体在人类中的病理生理作用需要进一步研究。
