Whole-Exome-Sequencing Reveals Small Deletions in CASP14 in Patients with Autosomal Recessive Inherited Ichthyosis.
Whole-Exome-Sequencing Reveals Small Deletions in CASP14 in Patients with Autosomal Recessive Inherited Ichthyosis.
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全外显子组测序揭示常染色体隐性遗传性鱼鳞病患者 CASP14 存在小缺失。
DOI：
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发表时间：
2017
影响因子：
3.6
通讯作者：
J. Fischer
中科院分区：
文献类型：
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作者：
P. Kirchmeier;A. Zimmer;B. Bouadjar;B. Rösler;J. Fischer
鱼鳞病是一组遗传异质性皮肤病，其特征是皮肤渗透性屏障紊乱，导致全身异常脱屑。人体皮肤的主要功能之一是保护身体免受脱水；因此，皮肤的水屏障严格调节经皮水分流失（TEWL）。 Oji 等人的最新命名法。 (1) 区分综合征型和非综合征型鱼鳞病；综合征性鱼鳞病相对容易诊断，因为它们与典型的其他症状（如毛发异常或神经缺陷）相关。非综合征性鱼鳞病分为3个亚组：（i）普通鱼鳞病，如寻常鱼鳞病和X连锁隐性鱼鳞病，这些鱼鳞病大多在出生时不存在； (ii) 角蛋白病性鱼鳞病，由 KRT1、KRT2 或 KRT10 基因突变引起； (iii) 常染色体先天性隐性鱼鳞病 (ARCI)，迄今为止已知有 8 种疾病相关基因突变：TGM1、ABCA12、ALOXE3、ALOX12B、CYP4F22、NIPAL4（Traupe 等人于 2014 年进行综述 (2)）、PNPLA1 (3) 和 CERS3 (4)。此外，Israel 等人还描述了临床上类似的非先天性鱼鳞病的 LIPN 突变。 （5）。利用单核苷酸多态性 (SNP) 基因分型和全外显子组测序 (WES)，我们在来自 2 个阿尔及利亚家族的 3 名轻度全身性鱼鳞病患者的 Caspase 14 (CASP14) 基因中发现了 2 个碱基对 (bp) (c.462_463delCA) 的缺失（图 S1a、b1）。预计该突变会导致移码，从而产生截短的蛋白质。迄今为止，已知有 11 种功能性人类半胱天冬酶（半胱氨酸天冬氨酸特异性蛋白酶）（半胱天冬酶 1-10 和半胱天冬酶 14）。它们中的大多数在细胞凋亡或炎症中发挥核心作用并且普遍表达。它们被合成为无活性的酶原，必须经过处理才能被激活。酶原由 N 端前结构域、大催化 (p17) 亚基和小非催化 (p11) 亚基组成。与其他半胱天冬酶相比，CASP14 不参与细胞凋亡或炎症，主要在表皮的所有基底上层中表达 (6)。在角质形成细胞分化过程中观察到 CASP14 表达和激活显着增加 (7)。在颗粒层中蛋白水解成熟后，CASP14 会降解角质层中的聚丝蛋白 (FLG) 单体，生成游离吸湿氨基酸 (aa)，即皮肤的天然保湿因子 (NMF) (8)。已知 FLG 突变会导致寻常鱼鳞病 (IV) (9)。 CASP14 的另一个功能是激活胰岛蛋白酶，这对于 saposin A 的成熟是必需的，saposin A 是一种参与皮肤渗透性屏障形成的鞘脂激活剂 (10)。最近，荣格等人。 (11) 描述了特应性皮炎 (AD) 患者中 CASP14 表达降低，这与皮肤屏障功能受损相关。
Ichthyoses are a genetically heterogeneous group of skin disorders characterized by a disturbed skin permeability barrier leading to an abnormal desquamation over the whole body. One of the major functions of the human skin is to protect the body against dehydration; therefore the water barrier of the skin strictly regulates transepidermal water loss (TEWL). The latest nomenclature of Oji et al. (1) distinguishes between syndromic and non-syndromic forms of ichthyoses; syndromic ichthyoses are relatively easy to diagnose due to their association with typical additional symptoms like hair abnormalities or neurological defects. The group of non-syndromic ichthyoses is divided into 3 subgroups: (i) common ichthyosis, such as ichthyosis vulgaris and X-linked recessive ichthyoses, which are mostly not present at birth; (ii) keratinopathic ichthyosis, which are caused by mutations in the genes KRT1, KRT2 or KRT10; and (iii) autosomal congenital recessive ichthyosis (ARCI), for which mutations in 8 disease-associated genes are known to date: TGM1, ABCA12, ALOXE3, ALOX12B, CYP4F22, NIPAL4 (reviewed in Traupe et al. 2014 (2)), PNPLA1 (3) and CERS3 (4). Additionally mutations in LIPN were described for a clinically similar non-congenital ichthyosis by Israeli et al. (5). Using single nucleotide polymorphism (SNP)-genotyping and whole-exome-sequencing (WES) we identified a deletion of 2 base pairs (bp) (c.462_463delCA) in the gene Caspase 14 (CASP14) in 3 patients with a mild form of generalized ichthyosis from 2 Algerian families (Fig. S1a, b1). The mutation is predicted to lead to a frame shift, resulting in a truncated protein. To date, 11 functional human caspases (cysteinylaspartate specific protease) are known (caspase 1–10 and caspase14). Most of them play a central role in apoptosis or inflammation and are ubiquitously expressed. They are synthesized as inactive zymogens and have to be processed to become activated. The zymogens consist of an N-terminal pro-domain, a large catalytic (p17) subunit and a small non-catalytic (p11) subunit. In contrast with other caspases CASP14 is not involved in apoptosis or inflammation and is mainly expressed in all suprabasal layers of the epidermis (6). A strong increase in CASP14 expression and activation has been observed during keratinocyte differentiation (7). After proteolytic maturation in the stratum granulosum, CASP14 degrades filaggrin (FLG) monomers in the stratum corneum to free hygroscopic amino acids (aa), the natural moisturizing factors (NMF) of the skin (8). FLG mutations are known to cause ichthyosis vulgaris (IV) (9). An additional function of CASP14 is the activation of mesotrypsin, which is necessary for the maturation of saposin A, a sphingolipid activator involved in the formation of the permeability barrier of the skin (10). Recently, Jung et al. (11) described a decreased CASP14 expression in patients with atopic dermatitis (AD) that correlates with an impaired skin barrier function.
影响因子：
6
作者：
Demerjian, Marianne;Hachem, Jean-Pierre;Feingold, Kenneth R.
通讯作者：
Feingold, Kenneth R.