Mutation-dependent effects on mRNA and protein expressions in cultured keratinocytes of Hailey-Hailey disease
Mutation-dependent effects on mRNA and protein expressions in cultured keratinocytes of Hailey-Hailey disease
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DOI：
10.1111/exd.12410
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发表时间：
2014-07-01
影响因子：
3.6
通讯作者：
Hashimoto, Takashi
中科院分区：
文献类型：
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作者：
Matsuda, Mitsuhiro;Hamada, Takahiro;Hashimoto, Takashi
Hailey-Hailey病（HHD）是一种由ATP 2C 1基因突变引起的显性遗传性皮肤病，ATP 2C 1基因编码分泌途径Ca 2 +/Mn 2 +-ATP酶蛋白1。确切的机制尚不清楚。在这项研究中，为了了解HHD的分子基础，我们检测了来自三个不同突变的HHD患者的培养角质形成细胞中mRNA和蛋白质的表达。我们发现p.Gln504X患者的mRNA和蛋白表达降低，而p.Pro307His和c.1308+1G>A患者的mRNA和蛋白表达不降低。对c.1308+1G>A患者的RT-PCR分析显示框内外显子跳跃。认为p.Gln504X中mRNA和蛋白质的减少是由无义介导的mRNA衰变引起的。p.Pro307His位于Ca ~（2+）结合残基附近，可引起构象变化，导致Ca ~（2+）转运缺陷。由c.1308+1G>A引起的框内较短转录物可能具有轻微降低的活性，这解释了患者的轻度表型。这些结果阐明了不同致病突变在皮肤病变发展中的致病作用。
Hailey-Hailey disease (HHD) is a dominantly inherited skin disease caused by mutations in ATP2C1 gene, which encodes secretory pathway Ca2+/Mn2+-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 Ca2+-binding residue may induced conformational change, which leads to defective Ca2+ 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.