Elevated stratum corneum hydrolytic activity in Netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides
Elevated stratum corneum hydrolytic activity in Netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides
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DOI：
10.1046/j.0022-202x.2001.01663.x
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发表时间：
2002-03-01
影响因子：
6.5
通讯作者：
Saijoh, K
中科院分区：
文献类型：
--
作者：
Komatsu, N;Takata, M;Saijoh, K
内瑟顿综合征是一种先天性鱼鳞病，伴有红皮病、毛干缺陷和特应性特征。在内瑟顿综合征患者中已发现分泌型丝氨酸蛋白酶抑制剂Kazal S型基因突变;然而，丝氨酸蛋白酶抑制剂Kazal 5型前蛋白的实际生理底物尚不清楚，遗传缺陷如何导致特征性皮肤表型仍不确定。在这里，我们描述了丝氨酸蛋白酶抑制剂Kazal-5型基因突变，包括两个新的无义突变，和基因型-表型相关性在三个内瑟顿综合征患者在两个无关的日本家庭。此外，基于丝氨酸蛋白酶抑制剂Kazal-5型前蛋白的结构的重新评估，正常角质形成细胞中羧肽酶的存在的证明，以及丝氨酸蛋白酶抑制剂Kazal-5型转录物在最上表皮以及毛囊皮脂腺单位中的mRNA定位的观察，我们提出了丝氨酸蛋白酶抑制剂Kazal的蛋白水解加工的假设模型，5型前蛋白在表皮和抑制调节角质细胞脱屑的丝氨酸蛋白酶抑制剂Kazal型5衍生肽的集合。这一假设得到了我们的内瑟顿综合征患者角质层样本中胰蛋白酶样水解活性显著增加的支持。本研究的结果表明，由于丝氨酸蛋白酶抑制剂Kazal-5型基因突变引起的脱屑抑制调节缺陷可能导致内瑟顿综合征中角质细胞过度脱屑，导致严重的皮肤渗透屏障功能障碍。
Netherton syndrome is a congenital ichthyosis associated with erythroderma, hair shaft defects, and atopic features. The mutations of the secretory serine protease inhibitor Kazal-type S gene have been identified in Netherton syndrome patients; however, the actual physiologic substrates of the serine protease inhibitor Kazal-type 5 proprotein are unknown, and how the genetic defects cause characteristic skin phenotype remains uncertain. Here, we describe the serine protease inhibitor Kazal-type 5 gene mutations, including two novel non-sense mutations, and genotype-phenotype correlation in three Netherton syndrome patients in two unrelated Japanese families. Furthermore, based on the reappraisal of the structure of the serine protease inhibitor Kazal-type 5 proprotein, demonstration of the presence of carboxypeptidase in normal keratinocytes, and the observation of mRNA localization of the serine protease inhibitor Kazal-type 5 transcripts in the uppermost epidermis as well as pilosebaceous units, we propose a hypothetical model of proteolytic processing of the serine protease inhibitor Kazal-type 5 proprotein in the epidermis and inhibitory regulation of corneocyte desquamation by a set of serine protease inhibitor Kazal-type 5-derived peptides. This hypothesis is supported by the marked increase of trypsin-like hydrolytic activity demonstrated in stratum corneum samples from our Netherton syndrome patients. The findings in this study suggest that the defective inhibitory regulation of desquamation due to the serine protease inhibitor Kazal-type 5 gene mutations may cause over-desquamation of corneocytes in Netherton syndrome, leading to severe skin permeability barrier dysfunction.