Mutations in SERPINB7, Encoding a Member of the Serine Protease Inhibitor Superfamily, Cause Nagashima-type Palmoplantar Keratosis
Mutations in SERPINB7, Encoding a Member of the Serine Protease Inhibitor Superfamily, Cause Nagashima-type Palmoplantar Keratosis
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DOI：
10.1016/j.ajhg.2013.09.015
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发表时间：
2013-11-07
影响因子：
9.8
通讯作者：
Amagai, Masayuki
中科院分区：
文献类型：
--
作者：
Kubo, Akiharu;Shiohama, Aiko;Amagai, Masayuki
“Nagashima型”掌跖角化病（NPPK）是一种常染色体隐性遗传的非综合征性弥漫性掌跖角化病，其特征在于界限清楚的弥漫性角化过度伴发红，扩展到手掌和足部的背侧表面以及跟腱区域。NPPK的过度角化是轻度和非进行性的，在临床上与Mal de Meleda相鉴别。我们对13个不相关的NPPK个体进行了全外显子组和/或桑格测序分析，并确定了SERPINB 7中的双等位基因推定功能丧失突变，SERPINB 7编码丝氨酸蛋白酶抑制剂超家族的细胞质成员。我们在日本和中国人群中发现了c.796C>T（p.Arg266*）的主要致病突变作为创始突变。SERPINB 7特异性存在于表皮的颗粒层和角质层（SC）的细胞质中。预测所有鉴定的突变体引起抑制蛋白酶的反应位点上游的提前终止，表明NPPK皮肤中SERPINB 7的蛋白酶抑制活性完全丧失。在将NPPK损伤皮肤暴露于水时，我们观察到SC中的发白海绵状变化，表明由于蛋白酶的过度活化和由此导致的SC结构完整性的丧失而导致水渗透到SC中。这些发现为开发NPPK的基于发病机制的疗法提供了重要的框架。
"Nagashima-type" palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area. Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda. We performed whole-exome and/or Sanger sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the serine protease inhibitor superfamily. We identified a major causative mutation of c.796C>T (p.Arg266*) as a founder mutation in Japanese and Chinese populations. SERPINB7 was specifically present in the cytoplasm of the stratum granulosum and the stratum corneum (SC) of the epidermis. All of the identified mutants are predicted to cause premature termination upstream of the reactive site, which inhibits the proteases, suggesting a complete loss of the protease inhibitory activity of SERPINB7 in NPPK skin. On exposure of NPPK lesional skin to water, we observed a whitish spongy change in the SC, suggesting enhanced water permeation into the SC due to overactivation of proteases and a resultant loss of integrity of the SC structure. These findings provide an important framework for developing pathogenesis-based therapies for NPPK.