Morizane Shin, Ouchida Mamoru, Sunagawa Ko, Sugimoto Saeko, Kobashi Mina, Sugihara Satoru, Nomura Hayato, Tsuji Kazuhide, Sato Atsushi, Miura Yoshihiro, Hattori Hiroaki, Tada Kotaro, Huh Wook-Kang, Seno Akemi, Iwatsuki Keiji
Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558,
Acta Med Okayama. 2018 Jun;72(3):275-282. doi: 10.18926/AMO/56073.
Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a large multidomain serine protease inhibitor that is expressed in epidermal keratinocytes. Nonsense mutations of the SPINK5 gene, which codes for LEKTI, cause Netherton syndrome, which is characterized by hair abnormality, ichthyosis, and atopy. A single nucleotide polymorphism (SNP) of SPINK5, p.K420E, is reported to be associated with the pathogenesis of atopic dermatitis (AD). We studied all 34 exons of the SPINK5 gene in Japanese 57 AD patients and 50 normal healthy controls. We detected nine nonsynonymous variants, including p.K420E; these variants had already been registered in the SNP database. Among them, p.R654H (n=1) was found as a heterozygous mutation in the AD patients, but not in the control. No new mutation was detected. We next compared the data of the AD patients with data from the Human Genetic Variation Database provided by Kyoto University; a significant difference was found in the frequency of the p.S368N genotype distribution. PolyPhen-2 and SIFT, two algorithms for predicting the functional effects of amino acid substitutions, showed significant scores for p.R654H. Therefore, R654H might be a risk factor for epidermal barrier dysfunction in some Japanese AD patients.
淋巴细胞上皮Kazal型相关抑制剂（LEKTI）是一种在表皮角质形成细胞中表达的大型多结构域丝氨酸蛋白酶抑制剂。编码LEKTI的SPINK5基因的无义突变会导致Netherton综合征，其特征为毛发异常、鱼鳞病和特应性。据报道，SPINK5的一个单核苷酸多态性（SNP），即p.K420E，与特应性皮炎（AD）的发病机制有关。我们研究了57例日本AD患者和50例正常健康对照者的SPINK5基因的所有34个外显子。我们检测到9个非同义变异，包括p.K420E；这些变异已在SNP数据库中登记。其中，p.R654H（n = 1）在AD患者中被发现为杂合突变，但在对照组中未发现。未检测到新的突变。接下来，我们将AD患者的数据与京都大学提供的人类遗传变异数据库的数据进行了比较；发现p.S368N基因型分布频率存在显著差异。PolyPhen-2和SIFT这两种预测氨基酸替代功能效应的算法对p.R654H显示出显著评分。因此，R654H可能是一些日本AD患者表皮屏障功能障碍的一个危险因素。
