Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling.
Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling.
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DOI：
10.1002/humu.21024
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发表时间：
2009-07
期刊：
影响因子：
3.9
通讯作者：
Toro, Jorge R.
中科院分区：
文献类型：
--
作者：
Blake, Patrick W.;Toro, Jorge R.
圆筒状瘤病（CYLD）基因的种系突变已经在圆柱体瘤、毛上皮瘤和/或螺旋腺瘤的家族中被描述。布鲁克-斯皮格勒综合征（BSS）是一种常染色体显性易感的皮肤附属肿瘤，包括圆柱状瘤、毛上皮瘤和/或螺旋腺瘤。现就BSS的临床特点、分子遗传学及动物模型作一综述。迄今为止，在73个不同民族和种族背景的家庭中，共报道了51个CYLD突变，发生在外显子9-20。在51个突变中，86%预计会导致蛋白质截断。迄今为止报道的7种错义突变仅发生在CYLD蛋白的泛素特异性蛋白酶（USP）结构域内，并且大多数只与多发性家族性毛上皮瘤相关。CYLD是一种肿瘤抑制基因。CYLD编码一种去泛素化（DUB）酶，负调控NF-kappaB和c-Jun n -末端激酶途径。CYLD DUB活性对赖氨酸63 （K63）连接的泛素（Ub）链具有高度特异性，但也被证明对k48连接的Ub链起作用。2008年，CYLD的USP结构域结晶，揭示了截断的Fingers亚结构域赋予CYLD对k63连接的泛素链的独特特异性。最近的动物模型研究揭示了CYLD在免疫、脂质代谢、精子发生、破骨细胞发生、抗微生物防御和炎症等方面的新作用。
Germline mutations in the cylindromatosis (CYLD) gene have been described in families with cylindromas, trichoepitheliomas, and/or spiradenomas. Brooke-Spiegler syndrome (BSS) is the autosomal dominant predisposition to skin appendageal neoplasms including cylindromas, trichoepitheliomas, and/or spiradenomas. We review the clinical features, molecular genetics, and the animal models of BSS. To date, a total of 51 CYLD mutations have been reported, occurring in exons 9–20, in 73 families with diverse ethnic and racial backgrounds. Of 51 mutations, 86% are expected to lead to truncated proteins. The seven missense mutations reported to date occur only within the ubiquitin-specific protease (USP) domain of the CYLD protein and most are associated exclusively with multiple familial trichoepithelioma. CYLD functions as a tumor suppressor gene. CYLD encodes a deubiquitinating (DUB) enzyme that negatively regulates the NF-kappaB and c-Jun N-terminal kinase pathways. CYLD DUB activity is highly specific for lysine 63 (K63)-linked ubiquitin (Ub) chains but has been shown to act on K48-linked Ub chains as well. In 2008 the CYLD USP domain was crystallized, revealing that the truncated Fingers subdomain confers CYLD’s unique specificity for K63-linked ubiquitin chains. Recent work using animal models revealed new roles for CYLD in immunity, lipid metabolism, spermatogenesis, osteoclastogenesis, anti-microbial defense and inflammation.
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影响因子：
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