The genetic basis of pachyonychia congenita
The genetic basis of pachyonychia congenita
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DOI：
10.1111/j.1087-0024.2005.10204.x
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发表时间：
2005-10-01
影响因子：
--
通讯作者：
McLean, WHI
中科院分区：
文献类型：
--
作者：
Smith, FJD;Liao, HH;McLean, WHI
1994年，先天性甲肥厚（PC）的分子基础被阐明。四种角蛋白基因与PC的主要亚型相关：K6 a或K16缺陷导致PC-1; K6 b或K17突变导致PC-2。角蛋白是上皮细胞特异性的中间丝蛋白，其突变导致细胞骨架网络异常，临床上表现为多种上皮细胞脆性表型。迄今为止，20个角蛋白基因的突变与人类疾病有关。在这里，我们回顾了PC的遗传基础，并报告了30个新的PC突变。其中，在PC-1家族中发现了25个突变，在PC-2激酶中发现了5个突变。所有的突变鉴定杂合氨基酸取代或小的框内缺失突变，除了一个不寻常的突变，在PC-1的散发病例。后者携带一个117 bp的重复，导致在K6 a的213结构域中插入39个氨基酸。还值得注意的是K17中的突变L388 P，这是在该蛋白的螺旋终止基序中鉴定的第一个遗传缺陷。了解这些疾病的遗传基础可以为患者提供更好的咨询，并为治疗开发铺平道路。
In 1994, the molecular basis of pachyonychia congenita (PC) was elucidated. Four keratin genes are associated with the major subtypes of PC: K6a or K16 defects cause PC-1; and mutations in K6b or K17 cause PC-2. Mutations in keratins, the epithelial-specific intermediate filament proteins, result in aberrant cytoskeletal networks which present clinically as a variety of epithelial fragility phenotypes. To date, mutations in 20 keratin genes are associated with human disorders. Here, we review the genetic basis of PC and report 30 new PC mutations. Of these, 25 mutations were found in PC-1 families and five mutations were identified in PC-2 kindreds. All mutations identified were heterozygous amino acid substitutions or small in-frame deletion mutations with the exception of an unusual mutation in a sporadic case of PC-1. The latter carried a 117 bp duplication resulting in a 39 amino acid insertion in the 213 domain of K6a. Also of note was mutation L388P in K17, which is the first genetic defect identified in the helix termination motif of this protein. Understanding the genetic basis of these disorders allows better counseling for patients and paves the way for therapy development.