PDF(Sci-hub)
Abstract：
Connexin 30 (Cx30), a member of the large gap-junction protein family, plays a role in the homeostasis of the epidermis and inner ear through gap junctional intercellular communication (GJIC). Here, we investigate the underlying mechanisms of four autosomal dominant Cx30 gene mutations that are linked to hearing loss and/or various skin diseases. First, the T5M mutant linked to non-syndromic hearing loss formed functional gap junction channels and hemichannels, similar to wild-type Cx30. The loss-of-function V37E mutant associated with Clouston syndrome or keratitis-ichthyosis-deafness syndrome was retained in the endoplasmic reticulum and significantly induced apoptosis. The G59R mutant linked to the Vohwinkel and Bart-Pumphrey syndromes was retained primarily in the Golgi apparatus and exhibited loss of gap junction channel and hemichannel function but did not cause cell death. Lastly, the A88V mutant, which is linked to the development of Clouston syndrome, also significantly induced apoptosis but through an endoplasmic-reticulum-independent mechanism. Collectively, we discovered that four unique Cx30 mutants might cause disease through different mechanisms that also likely include their selective trans-dominant effects on coexpressed connexins, highlighting the overall complexity of connexin-linked diseases and the importance of GJIC in disease prevention.
摘要：
连接蛋白30(Cx30),大间隙连接蛋白家族的成员，通过间隙连接细胞间通讯（GJIC）在表皮和内耳的稳态中起作用。这里,我们研究了与听力损失和/或各种皮肤病相关的4种常染色体显性Cx30基因突变的潜在机制.首先,与非综合征性听力损失相关的T5M突变体形成了功能性缝隙连接通道和半通道，与野生型Cx30相似。与克鲁斯顿综合征或角膜炎-鱼鳞病-耳聋综合征相关的功能丧失V37E突变体保留在内质网中并显着诱导细胞凋亡。与Vohwinkel和Bart-Pumphrey综合征相关的G59R突变体主要保留在高尔基体中，并表现出间隙连接通道和半通道功能的丧失，但不会引起细胞死亡。最后,A88V突变体,这与克鲁斯顿综合症的发展有关，也显着诱导细胞凋亡，但通过内质网非依赖性机制。总的来说，我们发现四种独特的Cx30突变体可能通过不同的机制引起疾病，这些机制也可能包括它们对共表达的连接蛋白的选择性反式显性效应，强调与连接蛋白相关的疾病的整体复杂性以及GJIC在疾病预防中的重要性。
