Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema
Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema
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DOI：
10.1038/ng2020
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发表时间：
2007-05-01
期刊：
影响因子：
30.8
通讯作者：
Irvine, Alan D.
中科院分区：
文献类型：
--
作者：
Sandilands, Aileen;Terron-Kwiatkowski, Ana;Irvine, Alan D.
我们最近报道了两种常见的聚丝蛋白（FLG）无效突变，导致寻常鱼鳞病（1）和易患湿疹和继发性过敏性疾病（2）。我们在这里表明，这些常见的欧洲突变是保守的单倍型上进行的祖先变异。为了便于对其他人群进行全面分析，我们报告了一种对这种大的、高度重复的基因进行全测序的策略，我们描述了15种变异，包括7种流行的变异。所有的变体都是无义突变或移码突变，在代表性的情况下，导致表皮中聚丝蛋白产生的损失。在爱尔兰的一项病例对照研究中，五种最常见的欧洲突变显示与中度至重度儿童湿疹密切相关（卡方检验：P = 2.12 x 10（-51）; Fisher精确检验：杂合子比值比（OR）= 7.44（95%置信区间（c. i.）= 4.9 - 11.3），纯合子OR 151（95%c. I. = 20 - 1，136））。我们在这个病例系列中发现了另外三个罕见的无效突变，这表明细丝蛋白相关的特应性皮炎的遗传结构由流行和罕见的风险等位基因组成。
We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris(1) and predispose to eczema and secondary allergic diseases(2). We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (chi(2) test: P = 2.12 x 10(-51); Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c. i.) = 4.9 - 11.3), and homozygote OR 151 (95% c. i. = 20 - 1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.