A HUMAN KERATIN-14 KNOCKOUT - THE ABSENCE OF K14 LEADS TO SEVERE EPIDERMOLYSIS-BULLOSA SIMPLEX AND A FUNCTION FOR AN INTERMEDIATE FILAMENT PROTEIN
A HUMAN KERATIN-14 KNOCKOUT - THE ABSENCE OF K14 LEADS TO SEVERE EPIDERMOLYSIS-BULLOSA SIMPLEX AND A FUNCTION FOR AN INTERMEDIATE FILAMENT PROTEIN
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DOI：
10.1101/gad.8.21.2574
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发表时间：
1994-11-01
影响因子：
10.5
通讯作者：
FUCHS, E
中科院分区：
文献类型：
--
作者：
CHAN, YM;ANTONLAMPRECHT, I;FUCHS, E
自发现以来，中间纤维（IF）的功能一直不清楚。在皮肤中，表皮细胞具有广泛的IF细胞骨架结构，由I型和II型角蛋白异源二聚体组成。这些蛋白质可能功能的线索来自最近的研究，表明几种常染色体显性的起泡皮肤疾病是由编码表皮角蛋白的基因缺陷引起的。这些疾病都表现出细胞变性和表达特定突变角蛋白基因的细胞中的角蛋白网络扰动。然而，从这些研究中尚不清楚细胞溶解是由于存在损害细胞生理学的大的不溶性角蛋白聚集体还是由于缺乏广泛的角蛋白细丝网络而引起的，这危及机械完整性。我们在这里报告一个非常罕见的情况下，严重的隐性单纯性大疱性表皮病（EBS）的分析，病人缺乏一个可辨别的角蛋白丝网络在基底表皮细胞。遗传分析显示，纯合子点突变，产生了一个提前终止密码子的主要基础I型角蛋白基因，并导致完全消融K14。近亲父母是正常的，每个人都携带一个无效K14突变拷贝。培养的角质形成细胞的分析使我们能够证明，K14的损失是不补偿的任何其他I型角蛋白的上调。当与体内研究一起显示由于缺乏广泛的基底角蛋白网络而产生的细胞脆性的存在时，这些发现提供了与体内缺乏IF蛋白相关的功能丧失的第一个明确证明。
Since their discovery, the function of intermediate filaments (IFs) has remained obscure. In skin, epidermal cells have extensive cytoskeletal architectures of IFs, composed of type I and type II keratin heterodimers. Clues to possible functions of these proteins have come from recent studies showing that several autosomal-dominant, blistering skin disorders are caused by defects in genes that encode epidermal keratins. These diseases all exhibit cell degeneration and keratin network perturbations in cells that express the particular mutant keratin gene. However, it is not clear from these studies whether cytolysis arises from the presence of large insoluble keratin aggregates that compromise cellular physiology or from the absence of an extensive keratin filament network, which jeopardizes mechanical integrity. We report here the analysis of an extremely rare case of severe recessive epidermolysis bullosa simplex (EBS), where the patient lacks a discernible keratin filament network in basal epidermal cells. Genetic analyses revealed a homozygous point mutation that yielded a premature termination codon in the major basal type I keratin gene and caused complete ablation of K14. The consanguineous parents were normal, each harboring one copy of the null K14 mutation. Analysis of cultured keratinocytes enabled us to document that the loss of K14 is not compensated for by the up-regulation of any other type I keratin. When taken together with the in vivo studies showing the presence of cell fragility generated from the lack of an extensive basal keratin network, these findings provide the first clear demonstration of loss of function associated with the absence of an IF protein in vivo.