Abstract：
Desmoplakin (DSP) is a desmosomal component expressed in skin and heart, essential for desmosome stability and intermediate filament connection. Pathogenic variants in the DSP gene encoding DSP, lead to heterogeneous skin, adnexa and heart-related phenotypes, including skin fragility, woolly hair (WH), palmoplantar keratoderma (PPK) and arrhythmogenic/dilated cardiomyopathy (ACM/DCM). The ambiguity of computer-based prediction analysis of pathogenicity and effect of DSP variants, indicates a necessity for functional analysis. Here, we report a heterozygous DSP variant that was not previously described, NM_004415.4:c.3337C>T (NM_004415.4(NP_004406.2):p.(Arg1113*)) in a patient with PPK, WH and ACM. RNA and protein analysis revealed ~50% reduction of DSP mRNA and protein expression. Patient\'s keratinocytes showed fragile cell-cell connections and perinuclear retracted intermediate filaments. Epidermal growth factor receptor (EGFR) is a transmembrane protein expressed in the basal epidermal layer involved in proliferation and differentiation, processes that are disrupted in the development of PPK, and in the regulation of the desmosome. In skin of the abovementioned patient, evident EGFR upregulation was observed. EGFR inhibition in patient\'s keratinocytes strongly increased DSP expression at the plasma membrane, improved intermediate filament connection with the membrane edges and reduced the cell-cell fragility. This cell phenotypic recovery was due to a translocation of DSP to the plasma membrane together with an increased number of desmosomes. These results indicate a therapeutic potential of EGFR inhibitors for disorders caused by DSP haploinsufficiency.
摘要：
Desmoplakin（DSP）是在皮肤和心脏中表达的桥粒成分，桥丝的稳定性和中间灯丝连接必不可少。DSP基因编码DSP的致病变异，导致皮肤不均匀，附件和心脏相关表型，包括皮肤脆弱,羊毛（WH），掌plant角化病（PPK）和致心律失常/扩张型心肌病（ACM/DCM）。基于计算机的DSP变异体致病性和效应预测分析的模糊性，表明了功能分析的必要性。这里,我们报告了一个以前没有描述过的杂合DSP变体，NM_004415.4：c.3337C>T（NM_004415.4（NP_004406.2）：p。（Arg1113*））在PPK患者中，WH和ACM。RNA和蛋白质分析显示DSPmRNA和蛋白质表达减少约50%。患者的角质形成细胞显示脆弱的细胞-细胞连接和核周缩回的中间丝。表皮生长因子受体(EGFR)是一种表达于表皮基底层的跨膜蛋白,参与细胞的增殖和分化。在PPK的发展中被破坏的过程，以及对细胞的调节。在上述患者的皮肤中，观察到明显的EGFR上调。患者角质形成细胞中的EGFR抑制强烈增加了质膜上的DSP表达，改善了中间细丝与膜边缘的连接，并降低了细胞-细胞的脆性。这种细胞表型恢复是由于DSP易位到质膜以及桥粒数量增加。这些结果表明EGFR抑制剂对于由DSP单倍体不足引起的病症的治疗潜力。
