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首页> 外文期刊>Molecular and Cellular Biology >Overcoming Functional Redundancy To Elicit Pachyonychia Congenita-Like Nail Lesions in Transgenic Mice
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Overcoming Functional Redundancy To Elicit Pachyonychia Congenita-Like Nail Lesions in Transgenic Mice

机译：克服功能冗余以诱发转基因小鼠先天性先天性指甲病

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Mutations affecting the coding sequence of intermediate filament (IF) proteins account for >30 disorders, including numerous skin bullous diseases, myopathies, neuropathies, and even progeria. The manipulation of IF genes in mice has been widely successful for modeling key features of such clinically distinct disorders. A notable exception is pachyonychia congenita (PC), a disorder in which the nail and other epithelial appendages are profoundly aberrant. Most cases of PC are due to mutations in one of the following keratin-encoding genes: K6, K16, and K17. Yet null alleles obliterating the function of both K6 genes (K6α and K6β) or the K17 gene, as well as the targeted expression of a dominant-negative K6α mutant, elicit only a subset of PC-specific epithelial lesions (excluding that of the nail in mice). We show that newborn mice null for K6α, K6β, and K17 exhibit severe lysis restricted to the nail bed epithelium, where all three genes are robustly expressed, providing strong evidence that this region of the nail unit is initially targeted in PC. Our findings point to significant redundancy among the multiple keratins expressed in hair and nail, which can be related to the common ancestry, clustered organization, and sequence relatedness of specific keratin genes.
机译：影响中间丝（IF）蛋白质编码序列的突变导致> 30种疾病，包括多种皮肤大疱性疾病，肌病，神经病，甚至早衰。在小鼠中对IF基因的操纵已被广泛成功地用于模拟这种临床上独特的疾病的关键特征。一个明显的例外是先天性肺炎（PCchyonychia congenita，PC），这种疾病中的指甲和其他上皮附件异常异常。 PC的大多数情况是由于以下角蛋白编码基因之一的突变：K6，K16和K17。然而，无效的等位基因消除了K6基因（K6α和K6β）或K17基因的功能以及显性阴性K6α突变体的靶向表达，仅引起PC特异性上皮病变的一部分（指甲除外）在小鼠中）。我们显示，对于K6α，K6β和K17无效的新生小鼠表现出严重的裂解，仅限于指甲床上皮细胞，其中所有三个基因都得到了强有力的表达，从而提供了有力的证据表明指甲单元的这一区域最初是在PC中靶向的。我们的研究结果表明，在头发和指甲中表达的多种角蛋白之间存在明显的冗余，这可能与特定角蛋白基因的共同血统，聚类组织和序列相关性有关。

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