Correlation between SPINK5 gene mutations and clinical manifestations in Netherton syndrome patients
Correlation between SPINK5 gene mutations and clinical manifestations in Netherton syndrome patients
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DOI：
10.1038/sj.jid.5701153
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发表时间：
2008-05-01
影响因子：
6.5
通讯作者：
Diamandis, Eleftherios P.
中科院分区：
文献类型：
--
作者：
Komatsu, Nahoko;Saijoh, Kiyofumi;Diamandis, Eleftherios P.
内瑟顿综合征（NS）是一种由丝氨酸蛋白酶抑制剂kazal - 5 （SPINK5）突变引起的先天性鱼鳞状皮肤病。组织钾化酶（KLKs）和淋巴上皮卡扎尔型相关抑制剂（LEKTI） （SPINK5产物）可能有助于皮肤中丝氨酸蛋白酶/抑制剂的平衡，并影响皮肤屏障功能和脱屑。SPINK5突变引起NS，导致LEKTI截断；每个NS患者具有不同长度的LEKTI，这取决于突变的位置。本研究旨在阐明日本NS患者的基因型/表型相关性，并表征每个LEKTI结构域的功能。由于我们无法在NS患者的组织中证明截断的蛋白质，我们使用重组蛋白来验证LEKTI长度与蛋白酶抑制活性相关的假设。基因型/表型与皮肤严重程度、生长迟缓、皮肤感染、角质层（SC）蛋白酶活性和SC中KLK水平存在相关性。LEKTI结构域对SC总蛋白酶活性的主要抑制作用是LEKTI结构域6-12的胰蛋白酶样（ph - ser - arg -）活性，结构域12-15的纤溶酶和胰蛋白酶样（pro - ph - arg -）活性，所有结构域的凝乳胰蛋白酶样活性，而对furin样活性无抑制作用。NS患者SC和血清中KLK水平显著升高。这些数据将LEKTI结构域缺陷与NS患者的临床表现联系起来，并指出了靶向治疗干预的可能性。
Netherton syndrome (NS) is a congenital ichthyosiform dermatosis caused by serine protease inhibitor Kazal-type 5 (SPINK5) mutations. Tissue kallikreins (KLKs) and lymphoepithelial Kazal-type-related inhibitor (LEKTI) (SPINK5 product) may contribute to the balance of serine proteases/inhibitors in skin and influence skin barrier function and desquamation. SPINK5 mutations, causing NS, lead to truncated LEKTI; each NS patient possesses LEKTI of a different length, depending on the location of mutations. This study aims to elucidate genotype/phenotype correlations in Japanese NS patients and to characterize the functions of each LEKTI domain. Since we were unable to demonstrate truncated proteins in tissue from patients with NS, we used recombinant protein to test the hypothesis that the length of LEKTI correlated with protease inhibitory activity. Genotype/phenotype correlations were observed with cutaneous severity, growth retardation, skin infection, stratum corneum (SC) protease activities, and KLK levels in the SC. Predominant inhibition by LEKTI domains against overall SC protease activities was trypsin-like (Phe-Ser-Arg-) activity by LEKTI domains 6-12, plasmin- and trypsin-like (Pro-Phe-Arg-) activities by domains 12-15, chymotrypsin-like activity by all domains, and furin-like activity by none. KLK levels were significantly elevated in the SC and serum of NS patients. These data link LEKTI domain deficiency and clinical manifestations in NS patients and pinpoints to possibilities for targeted therapeutic interventions.