Filaggrin mutations p.R501X and c.2282del4 in ichthyosis vulgaris
Filaggrin mutations p.R501X and c.2282del4 in ichthyosis vulgaris
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DOI：
10.1038/sj.ejhg.5201742
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发表时间：
2007-02-01
影响因子：
5.2
通讯作者：
Schmuth, Matthias
中科院分区：
文献类型：
--
作者：
Gruber, Robert;Janecke, Andreas R.;Schmuth, Matthias
寻常性鱼鳞病是人类最常见的遗传性角化病，其特征是皮肤的广泛性细鳞屑、手掌超线性伴或不伴毛发角化病和特应性。最近，IV的分子基础被归因于编码聚丝蛋白（FLG）的基因（即p.R501X和c. 2282del4.纯合子和复合杂合子受严重影响，而杂合子表现出轻微的疾病或无症状，这表明半显性遗传与不完全显性杂合子。我们报告了21例IV患者中有15例存在FLG突变，这些患者具有显著的广义缩放表型，其中包括一个四代家族的8名受影响成员。在这组患者中，不仅有纯合子和复合杂合子，而且还有p.R501X和c. 2282 del 4显示出明显的表型，而在六个个体中没有一个这两个突变是可检测的，尽管在两个患者中在免疫组织化学上的聚丝蛋白表达降低，表明FLG和/或其他基因中的其他突变仍有待鉴定。相反，来自大家族的另外两个p.R501X杂合子是无症状的。在来自西奥地利的对照人群中，合并了p.R501X和c. 2282例del 4携带者占5.45%（6/110）。我们证实，这些FLG变体是常见的，但我们的研究结果指出，存在额外的修饰符。
Ichthyosis vulgaris (IV) is the most common hereditary disorder of cornification in humans, characterized by generalized fine scaling of the skin, palmar hyperlinearity with or without keratosis pilaris and atopy. Recently, the molecular basis of IV was ascribed to loss-of-function mutations in the gene encoding filaggrin (FLG), namely p.R501X and c. 2282del4. Homozygotes and compound heterozygotes were severely affected whereas heterozygotes showed mild disease or were asymptomatic, suggesting semidominant inheritance with incomplete penetrance in heterozygotes. We report the presence of FLG mutations in 15 out of 21 IV patients with a marked generalized scaling phenotype, including eight affected members of a four-generation family. In this group of patients not only homozygous and compound heterozygous, but also heterozygous patients for p. R501X and c. 2282del4 display a pronounced phenotype, whereas in none of six individuals these two mutations were detectable despite decreased filaggrin expression on immunohistochemistry in two patients, indicating that other mutations in FLG and/or in other genes remain to be identified. In contrast, two additional p. R501X heterozygotes from the extended family are asymptomatic. In a control population from west-Austria a combined p. R501X and c. 2282del4 carrier frequency of 6/110 (5.45%) was observed. We confirm that these FLG variants are common, but our results point to the existence of additional modifiers.