Matsuda Mitsuhiro, Hamada Takahiro, Numata Sanae, Teye Kwesi, Okazawa Hiromi, Imafuku Shinichi, Ohata Chika, Furumura Minao, Hashimoto Takashi
Department of Dermatology, Kurume University School of Medicine, and Kurume University Institute of Cutaneous Cell Biology, Kurume, Japan.
Exp Dermatol. 2014 Jul;23(7):514-6. doi: 10.1111/exd.12410.
Hailey-Hailey disease (HHD) is a dominantly inherited skin disease caused by mutations in ATP2C1 gene, which encodes secretory pathway Ca(2+) /Mn(2+) -ATPase protein 1. The precise mechanism remains unclear. In this study, to understand molecular basis of HHD, we examined expression of mRNA and protein in cultured keratinocytes derived from three HHD patients with different mutations. We showed that reduced expression of mRNA and protein in patient with p.Gln504X, but not in patients with p.Pro307His and c.1308+1G>A. RT-PCR analysis for patient with c.1308+1G>A revealed in-frame exon skipping. Reduction of mRNA and protein in p.Gln504X was considered to be caused by nonsense-mediated mRNA decay. p.Pro307His located adjacent to Ca(2+) -binding residue may induced conformational change, which leads to defective Ca(2+) transport. In-frame shorter transcript caused by c.1308+1G>A may have slightly reduced activity, which accounted for mild phenotype of the patient. These results clarified the pathogenic effects of different causative mutations in development of skin lesions.
黑利-黑利病（HHD）是一种由ATP2C1基因突变引起的常染色体显性遗传性皮肤病，该基因编码分泌途径Ca(2+)/Mn(2+)-ATP酶蛋白1。确切机制尚不清楚。在本研究中，为了解HHD的分子基础，我们检测了三名具有不同突变的HHD患者来源的培养角质形成细胞中mRNA和蛋白质的表达。我们发现，携带p.Gln504X突变的患者中mRNA和蛋白质表达降低，但携带p.Pro307His和c.1308+1G>A突变的患者中未出现这种情况。对携带c.1308+1G>A突变的患者进行RT-PCR分析发现了框内外显子跳跃。p.Gln504X中mRNA和蛋白质的减少被认为是由无义介导的mRNA降解引起的。位于Ca(2+)结合残基附近的p.Pro307His可能诱导构象变化，从而导致Ca(2+)转运缺陷。由c.1308+1G>A引起的框内较短转录本可能活性略有降低，这解释了该患者的轻度表型。这些结果阐明了不同致病突变在皮肤病变发生过程中的致病作用。
