Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Hum Mutat. 2010 Mar;31(3):308-16. doi: 10.1002/humu.21189.
Plectin is a cytoskeletal linker protein that has a dumbbell-like structure with a long central rod and N- and C-terminal globular domains. Mutations in the gene encoding plectin (PLEC1) cause two distinct autosomal recessive subtypes of epidermolysis bullosa (EB): EB simplex with muscular dystrophy (EBS-MD), and EB simplex with pyloric atresia (EBS-PA). Here, we demonstrate that normal human fibroblasts express two different plectin isoforms including full-length and rodless forms of plectin. We performed detailed analysis of plectin expression patterns in six EBS-MD and three EBS-PA patients. In EBS-PA, expression of all plectin domains was found to be markedly attenuated or completely lost; in EBS-MD, the expression of the N- and C-terminal domains of plectin remained detectable, although the expression of rod domains was absent or markedly reduced. Our data suggest that loss of the full-length plectin isoform with residual expression of the rodless plectin isoform leads to EBS-MD, and that complete loss or marked attenuation of full-length and rodless plectin expression underlies the more severe EBS-PA phenotype. These results also clearly account for the majority of EBS-MD PLEC1 mutation restriction within the large exon 31 that encodes the plectin rod domain, whereas EBS-PA PLEC1 mutations are generally outside exon 31.
桥粒芯蛋白是一种细胞骨架连接蛋白，具有哑铃状结构，由长的中心杆和 N 端及 C 端球状结构域组成。桥粒芯蛋白基因（PLEC1）的突变导致两种不同的常染色体隐性遗传型大疱性表皮松解症（EB）：伴肌营养不良的单纯型大疱性表皮松解症（EBS-MD）和伴幽门闭锁的单纯型大疱性表皮松解症（EBS-PA）。本研究中，我们证实正常人类成纤维细胞表达两种不同的桥粒芯蛋白异构体，包括全长型和无杆型桥粒芯蛋白。我们对 6 例 EBS-MD 和 3 例 EBS-PA 患者的桥粒芯蛋白表达模式进行了详细分析。在 EBS-PA 中，所有桥粒芯蛋白结构域的表达均显著减弱或完全缺失；在 EBS-MD 中，桥粒芯蛋白的 N 端和 C 端结构域的表达仍可检测到，尽管杆状结构域的表达缺失或明显减少。我们的数据表明，全长桥粒芯蛋白异构体缺失而残留无杆桥粒芯蛋白异构体的表达导致 EBS-MD，而全长和无杆桥粒芯蛋白表达的完全缺失或显著减弱则导致更为严重的 EBS-PA 表型。这些结果还清楚地解释了大多数 EBS-MD PLEC1 突变限制在编码桥粒芯蛋白杆状结构域的大外显子 31 内，而 EBS-PA PLEC1 突变通常位于外显子 31 之外。
