Terron-Kwiatkowski A, Terrinoni A, Didona B, Melino G, Atherton D J, Irvine A D, McLean W H I
Ninewells Medical School, Dundee DD1 9SY, UK.
Br J Dermatol. 2004 Jun;150(6):1096-103. doi: 10.1111/j.1365-2133.2004.05967.x.
Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis characterized by epidermolytic hyperkeratosis strictly confined to the palms and soles, and usually associated with mutations in the keratin K9 gene (KRT9). Mutations in the keratin K1 gene (KRT1) have been shown to underlie a variety of phenotypes typically involving generalized epidermolytic hyperkeratosis, but in some cases the phenotype can be more regionally restricted.
To identify the genetic defect in two unrelated families initially presenting with EPPK but where careful examination revealed hyperkeratosis extending on to the proximal wrist flexure. Methods Linkage analysis and DNA sequencing.
We found that this phenotype is caused by a heterozygous missense mutation in the K1 gene, designated I479T. This mutation lies in the highly conserved helix termination motif of K1, previously shown to be important for keratin assembly and filament formation. In general, mutations in this region of keratins are associated with more severe disease phenotypes. However, K1 mutations in this region and the I479T mutation in particular have previously been associated with both severe and mild bullous congenital ichthyosiform erythroderma phenotypes. When further clinical enquiries were made, several affected individuals in the families studied here were found to have had transient flexural peeling and hyperkeratosis in the neonatal period.
K1 mutations may underlie a phenotype closely resembling EPPK. A history of transient flexural peeling and hyperkeratosis in childhood and palmoplantar keratoderma which extends beyond the boundary of the palmoplantar margins may indicate a K1 mutation rather than a K9 defect. As K1 mutations are also associated with severe widespread phenotypes, with important implications for prognostic and genetic counselling, whole body examination is recommended for patients presenting with EPPK.
表皮松解性掌跖角化病（EPPK）是一种常染色体显性遗传性皮肤病，其特征为表皮松解性角化过度，严格局限于手掌和足底，通常与角蛋白K9基因（KRT9）突变相关。角蛋白K1基因（KRT1）突变已被证明是多种表型的基础，这些表型通常涉及全身性表皮松解性角化过度，但在某些情况下，表型可能更局限于局部区域。
确定两个无关家族的遗传缺陷，这两个家族最初表现为EPPK，但仔细检查发现角化过度延伸至近端腕部屈侧。方法：连锁分析和DNA测序。
我们发现这种表型是由K1基因中的一个杂合错义突变引起的，命名为I479T。该突变位于K1高度保守的螺旋终止基序中，此前已证明该基序对角蛋白组装和丝状物形成很重要。一般来说，角蛋白这一区域的突变与更严重的疾病表型相关。然而，该区域的K1突变，特别是I479T突变，此前已与严重和轻度大疱性先天性鱼鳞病样红皮病表型相关。当进行进一步的临床询问时，发现这里研究的家族中的几个受影响个体在新生儿期有短暂的屈侧脱皮和角化过度。
K1突变可能是一种与EPPK非常相似的表型的基础。儿童期有短暂屈侧脱皮和角化过度病史以及掌跖角化病延伸至掌跖边缘以外，可能提示K1突变而非K9缺陷。由于K1突变也与严重的广泛表型相关，对预后和遗传咨询有重要意义，因此建议对表现为EPPK的患者进行全身检查。
