Recurrent mutations in kindlin-1, a novel keratinocyte focal contact protein, in the autosomal recessive skin fragility and photosensitivity disorder, Kindler syndrome
Recurrent mutations in kindlin-1, a novel keratinocyte focal contact protein, in the autosomal recessive skin fragility and photosensitivity disorder, Kindler syndrome
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DOI：
10.1046/j.0022-202x.2003.22136.x
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发表时间：
2004-01-01
影响因子：
6.5
通讯作者：
McGrath, JA
中科院分区：
文献类型：
--
作者：
Ashton, GHS;McLean, WHI;McGrath, JA
金德勒综合征 (OMIM 173650) 是一种罕见的常染色体隐性遗传疾病，其特征是创伤引起的水疱形成（尤其是在儿童期）和光过敏。其他特征包括皮肤粘膜疤痕和进行性皮肤异色症。皮肤和粘膜恶性肿瘤的风险也增加。该疾病最近被定位到 20p12.3，并在一个新基因 KIND1 中发现了致病突变。该基因编码 677 个氨基酸的蛋白质 kindlin-1，它是角质形成细胞中焦点接触的一个组成部分。在这项研究中，我们在来自巴基斯坦 (676insC)、英国高加索 (E304X)、阿曼 (W616X) 或意大利 (958-1G>A) 13 个家族的 16 名金德勒综合征患者中发现了 4 个新的 KIND1 复发突变。单倍型分析表明，每个突变都有共同的祖先突变等位基因，除了六个巴基斯坦家族之一，其中突变 676insC（发生在七个胞嘧啶的重复中）存在于不同的遗传背景中。除了三例英国白种人病例均为复合杂合子（第二个等位基因突变：L302X、1161delA、1909delA）外，所有突变均为纯合子。所有突变均与抗kindlin-1 抗体皮肤免疫染色显着减少或缺失相关。这些功能丧失的 KIND1 突变证明了 kindlin-1 在维持上皮完整性方面的重要性，尽管将该突变蛋白与光敏性和皮肤异色联系起来的机制仍有待确定。这些复发突变的描述也与优化来自特定种族背景的金德勒综合征患者的突变检测策略有关。
Kindler syndrome (OMIM 173650) is a rare autosomal recessive disorder characterized by trauma-induced blister formation (especially in childhood) and photosensitivity. Other features include mucocutaneous scarring and progressive poikiloderma. There is also an increased risk of skin and mucous membrane malignancy. The disorder was recently mapped to 20p12.3 and pathogenic mutations were identified in a new gene, KIND1. This gene encodes a 677 amino acid protein, kindlin-1, a component of focal contacts in keratinocytes. In this study, we identified four new recurrent mutations in KIND1 in 16 individuals with Kindler syndrome from 13 families of Pakistani (676insC), UK Caucasian (E304X), Omani (W616X), or Italian (958-1G>A) origins. Haplotype analysis demonstrated common ancestral mutant alleles for each mutation, apart from one of the six Pakistani families in which the mutation 676insC (which occurs in a repeat of seven cytosines) was present on a different genetic background. All mutations were homozygous, apart from the three UK Caucasian cases that were all compound heterozygotes (second allele mutations: L302X, 1161delA, 1909delA). All mutations were associated with markedly reduced or absent skin immunostaining with an antikindlin-1 antibody. These loss-of-function KIND1 mutations demonstrate the importance of kindlin-1 in maintaining epithelial integrity, although the mechanism linking this mutant protein to photosensitivity and poikiloderma remains to be determined. Delineation of these recurrent mutations is also relevant to optimizing mutation detection strategies in Kindler syndrome patients from particular ethnic backgrounds.