THE GENETIC-BASIS OF WEBER-COCKAYNE EPIDERMOLYSIS-BULLOSA SIMPLEX
THE GENETIC-BASIS OF WEBER-COCKAYNE EPIDERMOLYSIS-BULLOSA SIMPLEX
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DOI：
10.1073/pnas.90.15.7414
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发表时间：
1993-08-01
影响因子：
11.1
通讯作者：
FUCHS, E
中科院分区：
文献类型：
--
作者：
CHAN, YM;YU, QC;FUCHS, E
单纯大疱性表皮病是一组常染色体显性遗传的皮肤病，其特征是由于机械应力引起的基底表皮细胞变性而引起的水疱。最近，发现更严重的类型，Dowling-Meara和Koebner，是基底表皮角蛋白，角蛋白5（K5）和角蛋白14（K14）的遗传性疾病。在这里，我们表明，最温和的类型的EBS，韦伯-科凯恩，也是这些角蛋白的疾病。两个无亲缘关系的Weber-Cockayne型EBS家系的成员在两个K5等位基因中的一个的密码子161的第二个碱基位置上存在T -> G点突变，导致Ile -> Ser突变。这种突变不存在于未受影响的成员或来自正常个体的156个等位基因中。连锁分析将缺陷定位于染色体12 q11-q13上的II型角蛋白基因簇（在θ = 0的3.0处的优势分数的峰值对数），提供了强有力的额外证据，该突变是Weber-Cockayne EBS表型的原因。Ile-161在K5的非螺旋头部结构域中，该区域先前被证明对10 nm细丝组装很重要。该突变产生了一个潜在的蛋白激酶C的底物位点，这可能会影响中间丝结构，可能导致在突变患者的超微结构中观察到的丝内缔合。
Epidermolysis bullosa simplex (EBS) is a group of autosomal dominant skin diseases characterized by blistering, due to mechanical-stress-induced degeneration of basal epidermal cells. Recently, it was discovered that the more severe types, Dowling-Meara and Koebner, are genetic disorders of the basal epidermal keratins, keratin 5 (K5) and keratin 14 (K14). Here, we show that the mildest type of EBS, Weber-Cockayne, is also a disorder of these keratins. Affected members of two unrelated families with Weber-Cockayne EBS had a T --> G point mutation in the second base position of codon 161 of one of two K5 alleles, leading to an Ile --> Ser mutation. This mutation was not present in unaffected members or in 156 alleles from normal individuals. Linkage analyses mapped the defect to the type II keratin gene cluster on chromosome 12q11-q13 (peak logarithm of odds score at theta = 0 of 3.0), providing strong additional evidence that this mutation is responsible for the Weber-Cockayne EBS phenotype. Conserved among type II keratins, Ile-161 is in the nonhelical head domain of K5, a region previously shown to be important for 10-nm filament assembly. The mutation generates a potential substrate site for protein kinase C, which could influence intermediate filament architecture, perhaps leading to the intrafilament association seen ultrastructurally in patients with the mutation.