The genetic basis of epidermolysis bullosa simplex with mottled pigmentation
The genetic basis of epidermolysis bullosa simplex with mottled pigmentation
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DOI：
10.1073/pnas.93.17.9079
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发表时间：
1996-08-20
影响因子：
11.1
通讯作者：
Fuchs, E
中科院分区：
文献类型：
--
作者：
Uttam, J;Hutton, E;Fuchs, E
单纯性大疱性表皮松解症(EBS)是一组常染色体显性遗传性皮肤病，以水疱性皮肤病为特征，由机械应激引起的基底层表皮细胞变性引起，现已公认的三大亚型是基表皮角蛋白、角蛋白5(K5)和角蛋白14(K14)的遗传性疾病。在这里，我们发现一种罕见的亚型，称为斑驳色素沉着(MP)，也是这些角蛋白的一种疾病，两个看似不相关的EBS-MP家系的受累成员在两个K5等位基因之一的24号密码子的第二个碱基位置上发生了C到T点突变，导致了Pro：Leu突变。这种突变在未受影响的成员中不存在，在正常个体的100个等位基因中也不存在。连锁分析将该缺陷定位于位于染色体12q11-q13上的II型角蛋白基因(优势分数的峰值对数在phi=0的3.9)。这提供了强有力的证据表明该突变导致了EBS-MP表型，仅在K5和K6之间保守，而不在其他任何II型角蛋白中，Pro-24位于K5的非螺旋头域，并且仅轻微扰动在体外组装的10 nm角蛋白细丝的长度，然而，K5头域的这一部分很可能突出在丝状表面，可能导致在中间丝状结构和/或黑素小体分布中额外的像差，在超微结构上可在该突变的患者中看到。
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, It is now well-established that the three major subtypes of EBS are genetic disorders of the basal epidermal keratins, keratin 5 (K5) and keratin 14 (K14). Here we show that a rare subtype, referred to as EBS with mottled pigmentation (MP), is also a disorder of these keratins, Affected members of two seemingly unrelated families with EBS-MP had a C to T point mutation in the second base position of codon 24 of one of two K5 alleles, leading to a Pro:Leu mutation. This mutation was not present in unaffected members nor in 100 alleles from normal individuals. Linkage analyses mapped the defect to this type II keratin gene (peak logarithm of odds score at phi = 0 of 3.9), which is located on chromosome 12q11-q13. This provides strong evidence that this mutation is responsible for the EBS-MP phenotype, Only conserved between K5 and K6, and not among any of the other type II keratins, Pro-24 is in the nonhelical head domain of K5, and only mildly perturbs the length of 10-nm keratin filaments assembled in vitro, However, this part of the K5 head domain is likely to protrude on the filament surface, perhaps leading to additional aberrations in intermediate filament architecture and/or in melanosome distribution that are seen ultrastructurally in patients with the mutation.