Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3
Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3
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DOI：
10.1093/hmg/ddi491
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发表时间：
2006-03-01
影响因子：
3.5
通讯作者：
Fischer, J
中科院分区：
文献类型：
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作者：
Lefèvre, C;Bouadjar, B;Fischer, J
我们报道了一种非综合征型常染色体隐性遗传先天性鱼鳞病（ARCI）的突变在一个新的基因定位中被发现，该基因位于染色体19p12-q12上，在OMIM数据库（MIM 604777）中被定义为LI3。表型通常表现为板层状鱼鳞病和手掌和脚底的超线性。来自阿尔及利亚、法国、意大利和黎巴嫩的12个近亲家庭的21例患者，在19p12染色体上发现了一个新基因FLJ39501的7个纯合突变，包括5个错义突变和2个缺失。FLJ39501编码的蛋白为细胞色素P450，家族4，F亚家族，白三烯b4 -omega-羟化酶（CYP4F2）的多肽2同源蛋白，可通过12(R)-脂氧合酶途径催化trioxilin A3的20-羟基化。这种底物被脂肪醇：烟酰胺-腺嘌呤二核苷酸氧化还原酶（FAO）酶复合物进一步氧化，其中一种成分ALDH3A2已知在Sjogren-Larsson综合征（以鱼斑病和痉挛性截瘫为特征）中发生突变，将导致20-羧基-(R)-三oxilin A3。这种化合物可能与皮肤水合作用有关，是大多数形式的ARCI中必不可少的缺失产品。其手性同系物20-羧基-(S)-trioxilin A3可能与痉挛性截瘫和维持神经元完整性有关。
We report the identification of mutations in a non-syndromic autosomal recessive congenital ichthyosis (ARCI) in a new gene mapping within a previously identified locus on chromosome 19p12-q12, which has been defined as LI3 in the OMIM database (MIM 604777). The phenotype usually presents as lamellar ichthyosis and hyperlinearity of palms and soles. Seven homozygous mutations including five missense mutations and two deletions were identified in a new gene, FLJ39501, on chromosome 19p12 in 21 patients from 12 consanguineous families from Algeria, France, Italy and Lebanon. FLJ39501 encodes a protein which was found to be a cytochrome P450, family 4, subfamily F, polypeptide 2 homolog of the leukotriene B4-omega-hydroxylase (CYP4F2) and could catalyze the 20-hydroxylation of trioxilin A3 from the 12(R)-lipoxygenase pathway. Further oxidation of this substrate by the fatty alcohol:nicotinamide-adenine dinucleotide oxidoreductase (FAO) enzyme complex, in which one component, ALDH3A2, is known to be mutated in Sjogren-Larsson syndrome (characterized by ichthyosis and spastic paraplegia), would lead to 20-carboxy-(R)-trioxilin A3. This compound could be involved in skin hydration and would be the essential missing product in most forms of ARCI. Its chiral homolog, 20-carboxy-(S)-trioxilin A3, could be implicated in spastic paraplegia and in the maintenance of neuronal integrity.