PDF(Pubmed)
Abstract：
UNASSIGNED: Arrhythmogenic cardiomyopathy can be caused by genetic variants in desmosomal cadherins. Since cardiac desmosomal cadherins are crucial for cell-cell-adhesion, their correct localization at the plasma membrane is essential.
UNASSIGNED: Nine desmocollin-2 variants at five positions from various public genetic databases (p.D30N, p.V52A/I, p.G77V/D/S, p.V79G, p.I96V/T) and three additional conserved positions (p.C32, p.C57, p.F71) within the prodomain were investigated in vitro using confocal microscopy. Model variants (p.C32A/S, p.V52G/L, p.C57A/S, p.F71Y/A/S, p.V79A/I/L, p.I96l/A) were generated to investigate the impact of specific amino acids.
UNASSIGNED: We revealed that all analyzed positions in the prodomain are critical for the intracellular transport. However, the variants p.D30N, p.V52A/I and p.I96V listed in genetic databases do not disturb the intracellular transport revealing that the loss of these canonical sequences may be compensated.
UNASSIGNED: As disease-related homozygous truncating desmocollin-2 variants lacking the transmembrane domain are not localized at the plasma membrane, we predict that some of the investigated prodomain variants may be relevant in the context of arrhythmogenic cardiomyopathy due to disturbed intracellular transport.
UNASSIGNED: Nine desmocollin-2 variants at five positions from various public genetic databases (p.D30N, p.V52A/I, p.G77V/D/S, p.V79G, p.I96V/T) and three additional conserved positions (p.C32, p.C57, p.F71) within the prodomain were investigated in vitro using confocal microscopy. Model variants (p.C32A/S, p.V52G/L, p.C57A/S, p.F71Y/A/S, p.V79A/I/L, p.I96l/A) were generated to investigate the impact of specific amino acids.
UNASSIGNED: We revealed that all analyzed positions in the prodomain are critical for the intracellular transport. However, the variants p.D30N, p.V52A/I and p.I96V listed in genetic databases do not disturb the intracellular transport revealing that the loss of these canonical sequences may be compensated.
UNASSIGNED: As disease-related homozygous truncating desmocollin-2 variants lacking the transmembrane domain are not localized at the plasma membrane, we predict that some of the investigated prodomain variants may be relevant in the context of arrhythmogenic cardiomyopathy due to disturbed intracellular transport.
摘要：
■致心律失常性心肌病可由桥粒钙粘蛋白的遗传变异引起。由于心脏桥粒钙粘蛋白对于细胞-细胞粘附至关重要，它们在质膜上的正确定位至关重要。
■来自各种公共遗传数据库的五个位置的九个desmocollin-2变体（p。D30N,p.V52A/I,p.G77V/D/S,p.V79G,p.I96V/T）和三个额外的保守位置（p。使用共聚焦显微镜在体外研究了前结构域内的C32，p.C57，p.F71）。模型变体（p。C32A/S,p.V52G/L,p.C57A/S,p.F71Y/A/S,p.V79A/I/L,产生p.I96l/A）以研究特定氨基酸的影响。
■我们揭示了前结构域中所有分析的位置对于细胞内运输至关重要。然而,变体p.D30N，遗传数据库中列出的p.V52A/I和p.I96V不干扰细胞内运输，表明可以补偿这些规范序列的丢失。
■由于缺乏跨膜结构域的疾病相关纯合子截短桥粒胶原蛋白-2变体未定位在质膜上，我们预测,由于细胞内转运紊乱,一些研究的前结构域变异可能与致心律失常性心肌病相关.
■来自各种公共遗传数据库的五个位置的九个desmocollin-2变体（p。D30N,p.V52A/I,p.G77V/D/S,p.V79G,p.I96V/T）和三个额外的保守位置（p。使用共聚焦显微镜在体外研究了前结构域内的C32，p.C57，p.F71）。模型变体（p。C32A/S,p.V52G/L,p.C57A/S,p.F71Y/A/S,p.V79A/I/L,产生p.I96l/A）以研究特定氨基酸的影响。
■我们揭示了前结构域中所有分析的位置对于细胞内运输至关重要。然而,变体p.D30N，遗传数据库中列出的p.V52A/I和p.I96V不干扰细胞内运输，表明可以补偿这些规范序列的丢失。
■由于缺乏跨膜结构域的疾病相关纯合子截短桥粒胶原蛋白-2变体未定位在质膜上，我们预测,由于细胞内转运紊乱,一些研究的前结构域变异可能与致心律失常性心肌病相关.
