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Abstract：
Dominant and recessive mutations in the desmosomal cadherin, desmoglein (DSG) 1, cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, respectively. In this study, we compare two dominant missense mutations in the DSG1 transmembrane domain (TMD), G557R and G562R, causing PPK (DSG1PPK-TMD) and SAM syndrome (DSG1SAM-TMD), respectively, to determine the differing pathomechanisms of these mutants. Expressing the DSG1TMD mutants in a DSG-null background, we use cellular and biochemical assays to reveal the differences in the mechanistic behavior of each mutant. Super-resolution microscopy and functional assays showed a failure by both mutants to assemble desmosomes due to reduced membrane trafficking and lipid raft targeting. DSG1SAM-TMD maintained normal expression levels and turnover relative to wildtype DSG1, but DSG1PPK-TMD lacked stability, leading to increased turnover through lysosomal and proteasomal pathways and reduced expression levels. These results differentiate the underlying pathomechanisms of these disorders, suggesting that DSG1SAM-TMD acts dominant negatively, whereas DSG1PPK-TMD is a loss-of-function mutation causing the milder PPK disease phenotype. These mutants portray the importance of the DSG TMD in desmosome function and suggest that a greater understanding of the desmosomal cadherin TMDs will further our understanding of the role that desmosomes play in epidermal pathophysiology.
摘要：
桥粒钙粘蛋白的显性和隐性突变，桥粒蛋白（DSG）1，引起皮肤疾病掌planar角化症（PPK）和严重的皮炎，多种过敏,代谢消耗（SAM）综合征，分别。在这项研究中,我们比较了DSG1跨膜结构域（TMD）中的两个显性错义突变，G557R和G562R,引起PPK（DSG1PPK-TMD）和SAM综合征（DSG1SAM-TMD），分别,以确定这些突变体的不同病理机制。在DSG-null背景中表达DSG1TMD突变体，我们使用细胞和生化分析来揭示每个突变体的机械行为的差异。超分辨率显微镜和功能测定显示，由于膜运输和脂质筏靶向减少，两种突变体都未能组装桥粒。DSG1SAM-TMD维持相对于野生型DSG1的正常表达水平和更替，但DSG1PPK-TMD缺乏稳定性，导致通过溶酶体和蛋白酶体途径增加的周转和降低的表达水平。这些结果区分了这些疾病的潜在病理机制，这表明DSG1SAM-TMD负向主导，而DSG1PPK-TMD是导致轻度PPK疾病表型的功能丧失突变。这些突变体描绘了DSGTMD在桥粒功能中的重要性，并表明对桥粒钙粘蛋白TMD的更多了解将进一步了解桥粒在表皮病理生理学中的作用。
