Conditional Alox12b knockout: degradation of the corneocyte lipid envelope in a mouse model of autosomal recessive congenital ichthyoses.
Conditional Alox12b knockout: degradation of the corneocyte lipid envelope in a mouse model of autosomal recessive congenital ichthyoses.
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条件性 Alox12b 敲除：常染色体隐性先天性鱼鳞病小鼠模型中角质细胞脂质包膜的降解
DOI：
10.1016/j.jid.2019.06.134
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Schneider
中科院分区：
文献类型：
--
作者：
Angela;Latzko;Susanne;Rosenberger;Sabine;Crumrine;Hielscher;Thomas;Peter M;Manfred;Schneider
常染色体隐性遗传性先天性鱼鳞病的皮肤屏障缺陷导致出生后立即过多的经皮失水。受影响的婴儿通常出生为胶凝婴儿，反映了对渗透性屏障缺陷的物理补偿。然而，在现有的基因敲除小鼠模型中，子宫外存活时间被限制在几个小时内。因此，这些动物不允许对任何产后治疗进行评估。据报道，10种不同基因的突变可导致常染色体隐性先天性鱼鳞病（Hotz et al., 2018）。其中7个编码的蛋白质参与了ω-羟基神经酰胺（ω-OH-Cer）的生物合成，因此参与了角质细胞脂质包膜的形成。TGM1是最常受影响的基因，它编码转谷氨酰胺酶-1，这是一种交联角质包膜（CE）蛋白的酶，可能在角质细胞脂质包膜形成中发挥作用（Crumrine et al., 2019）。常染色体隐性遗传的先天性鱼鳞病目前还没有治愈方法。对症治疗以润肤剂为基础，辅以角化剂，如有需要，还可进行全身类维生素a治疗。为了阐明致病过程，需要忠实地概括该疾病主要特征的动物模型。我们分别建立了编码12R-LOX的Alox12b （Epp et al., 2007）和编码12R-LOX -3的Aloxe3 （Krieg et al., 2013）的传统敲除小鼠模型。这证实了12R-LOX和eLOX-3对ω-OH-Cer的亚油酸部分的连续氧合是ω-OH-Cer生物合成的关键步骤。纯合子基因敲除小鼠由于过早死亡，没有发育出典型的鱼鳞样表型。
The skin barrier defect underlying autosomal recessive congenital ichthyoses leads to excessive transepidermal water loss immediately after birth. Affected infants are often born as collodion babies reflecting a physical compensation for the defective permeability barrier. In the available knockout mouse models, however, extrauterine survival is limited to a few hours. These animals, therefore, do not allow evaluation of any postnatal therapy.Mutations in 10 different genes have been reported to cause autosomal recessive congenital ichthyoses (Hotz et al., 2018). Seven of them encode proteins involved in the biosynthesis of omega-hydroxyceramides (ω-OH-Cer) and, thus, in the formation of the corneocyte lipid envelope. TGM1, the most frequently affected gene, codes for transglutaminase-1, an enzyme that cross-links cornified envelope (CE) proteins and might play a role in corneocyte lipid envelope formation (Crumrine et al., 2019). There is no cure for autosomal recessive congenital ichthyoses yet. Symptomatic treatment is based on emollients, complemented by keratolytic agents and, if needed, systemic retinoid therapy. To elucidate pathogenic processes, animal models that faithfully recapitulate the cardinal features of the disease are required. We developed traditional knockout mouse models for Alox12b (Epp et al., 2007) and Aloxe3 (Krieg et al., 2013) encoding 12R-LOX and eLOX-3, respectively. Constitutive inactivation of either gene resulted in a rapidly fatal water loss, confirming that the successive oxygenation of the linoleate moiety of omega-hydroxyacyl-sphingosines by 12R-LOX and eLOX-3 is a crucial step in the biosynthesis of ω-OH-Cer. Homozygous knockout mice did not develop a typical ichthyosiform phenotype because they died too early.
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常染色体隐性遗传先天性鱼鳞病小鼠器官组织培养模型
影响因子：
10.3
作者：
Rosenberger;Latzko;Hausser;Schneider
通讯作者：
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影响因子：
14.9
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The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
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