Smith Frances J D, Irvine Alan D, Terron-Kwiatkowski Ana, Sandilands Aileen, Campbell Linda E, Zhao Yiwei, Liao Haihui, Evans Alan T, Goudie David R, Lewis-Jones Sue, Arseculeratne Gehan, Munro Colin S, Sergeant Ann, O'Regan Gráinne, Bale Sherri J, Compton John G, DiGiovanna John J, Presland Richard B, Fleckman Philip, McLean W H Irwin
Epithelial Genetics Group, Human Genetics Unit, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.
Nat Genet. 2006 Mar;38(3):337-42. doi: 10.1038/ng1743. Epub 2006 Jan 29.
Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of approximately 4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.
寻常型鱼鳞病（OMIM 146700）是最常见的遗传性角化障碍疾病，也是人类最常见的单基因疾病之一。基于对6051名健康英国学童的调查，最常被引用的发病率为1/250。我们已经确定，在15个家族中，编码聚角蛋白微丝蛋白（FLG）的基因中的纯合或复合杂合突变R501X和2282del4是中度或重度寻常型鱼鳞病的病因。此外，这些突变具有半显性；杂合子表现出非常轻微的表型，且外显率不完全。在欧洲血统人群中，这些突变的组合等位基因频率约为4%，这解释了寻常型鱼鳞病的高发病率。前聚角蛋白微丝蛋白是表皮中透明角质颗粒的主要蛋白质。在终末分化过程中，它被切割成多个聚角蛋白微丝蛋白肽，这些肽聚集角蛋白丝。形成的基质交联形成角质化细胞包膜的主要成分。我们发现，这种主要结构蛋白的缺失或减少会导致不同程度的角化受损。
