Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis
Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis
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DOI：
10.1002/humu.20236
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发表时间：
2005-10-01
期刊：
影响因子：
3.9
通讯作者：
Hennies, HC
中科院分区：
文献类型：
--
作者：
Eckl, KM;Krieg, P;Hennies, HC
常染色体隐性先天性鱼鳞病（ARCI）是一种临床和遗传异质性的严重遗传性角化疾病，其特征是整个被膜的严重鳞屑，颜色和形状的差异。它常伴有红斑。迄今为止，已有6个ARCI基因座。已被映射。最近在土耳其、法国和北非的鱼鳞状红皮病患者中发现了编码两种不同表皮脂氧合酶的17p13染色体上ALOXE3和ALOX12B的突变。在这里，我们描述了来自中欧、土耳其和印度次大陆的17个ARCI家族的分子和临床发现，这些家族具有ALOXE3或ALOX12B突变。我们在ALOX12B中发现了11个新的点突变（1个无义突变和10个错义突变）和ALOXE3中4个不同的失活突变。ALOX12B和ALOXE3的基因产物分别是表皮脂氧合酶12R-LOX和eLOX3，它们优先在皮肤中合成。它们依次通过12(R)-HPETE将花生四烯酸转化为相应的环氧醇、8(R)-羟基、11(R)、12(R)-环氧二碳三烯酸。为了评估酶活性的损害，我们在体外表达了突变基因，并测定了重组蛋白对其真正底物的活性。除了一种重组突变体外，其他所有突变体都是酶失活的。ALOXE3和ALOX12B致病突变的特征和由此产生的ARCI表型没有明确的诊断标准；然而，我们发现了遗传结果与鱼鳞病临床表现之间的第一个相关性。
Autosomal,recessive congenital ichthyosis (ARCI) is a clinically and genetically heterogeneous group of severe hereditary keratinization disorders characterized by intense scaling of the whole integument, and differences in color and shape. It is often associated with erythema. To date, six loci for ARCI. have been mapped. Mutations in ALOXE3 and ALOX12B on chromosome 17p13, which code for two different epidermal lipoxygenases, were recently found in patients with ichthyosiform erythroderma from Turkey, France, and North Africa. Here we describe molecular and clinical findings in 17 families with ARCI originating from Central Europe, Turkey, and the Indian subcontinent, with mutations in ALOXE3 or ALOX12B. We identified 11 novel point mutations in ALOX12B (one nonsense mutation and 10 missense mutations) and four different inactivating mutations in ALOXE3. The gene products of ALOX12B and ALOXE3, the epidermal lipoxygenases 12R-LOX and eLOX3 respectively, are preferentially synthesized in the skin. They act in sequence to convert arachidonic acid via 12(R)-HPETE to the corresponding epoxyalcohol, 8(R)-hydroxy,11(R),12(R)-epoxyeicosatrienoic acid. To assess the impairment of enzyme activity, we expressed the mutated genes in vitro and determined the activity of the recombinant proteins toward their genuine substrates. All but one of the recombinant mutants were enzymatically inactive. The characterization of disease-causing mutations in ALOXE3 and ALOX12B and the resulting ARCI phenotypes did not result in clear diagnostic criteria; however, we found a first correlation between the genetic findings and the clinical presentation of ichthyosis.