Molecular analysis of connexin26 asparagine14 mutations associated with syndromic skin phenotypes
Molecular analysis of connexin26 asparagine14 mutations associated with syndromic skin phenotypes
复制标题
DOI：
10.1111/j.1600-0625.2010.01222.x
复制
发表时间：
2011-05-01
影响因子：
3.6
通讯作者：
van Steensel, Maurice A. M.
中科院分区：
文献类型：
--
作者：
de Zwart-Storm, Eugene A.;Rosa, Rafael F. M.;van Steensel, Maurice A. M.
连接蛋白26是一种皮肤间隙连接蛋白，其突变可引起多种皮肤疾病，包括角膜炎-鱼鳞病-耳聋综合征（KID）。我们先前描述了一种与KID不同的表型，即低血压-耳聋综合征，由连接蛋白26中的突变p.Asn14Lys引起。然而，据报道，同一位置的不同突变p.Asn14Tyr会导致类似于KID的疾病。不同的取代导致蛋白质不同的构象变化，每种变化对其行为都有独特的影响。这可以解释表型差异。我们在巴西和波兰的两名患者中发现了先前描述的连接蛋白26突变p.Asn14Tyr，并观察到与经典KID综合征截然不同的表型。我们评估了p.Asn14Tyr和p.Asn14Lys的功能后果，使用荧光标记蛋白和降落伞试验，将其与经典的KID突变p.Asp50Asn进行比较。我们的分析表明，p.Asn14Tyr，p.Asn14Lys和p.Asp50Asn对蛋白定位和间隙连接通透性有不同的结果。然而，我们观察到的表型之间的差异不能很容易地解释从蛋白质运输或间隙连接通透性的影响。
Mutations in connexin26, a cutaneous gap junction protein, cause a wide variety of skin disorders including keratitis-ichthyosis-deafness syndrome (KID). We previously delineated a phenotype distinct from KID, hypotrichosis-deafness syndrome, caused by the mutation p.Asn14Lys in connexin26. However, a different mutation at the same location, p.Asn14Tyr, was reported to cause a disorder similar to KID. Distinct substitutions cause different conformational changes to the protein, each with unique consequences for its behaviour. This may explain the phenotypic differences. We found the previously described mutation p.Asn14Tyr in connexin26 in two patients from Brazil and Poland, and observe quite distinct phenotypes distinguishable from classical KID syndrome. We assessed functional consequences of p.Asn14Tyr and p.Asn14Lys, using fluorescently labelled proteins and parachute assay, comparing them with the classical KID mutation p.Asp50Asn. Our analyses show that p.Asn14Tyr, p.Asn14Lys and p.Asp50Asn have different consequences for protein localization and gap junction permeability. However, the differences between the phenotypes we observed cannot be readily explained from effects on protein trafficking or gap junction permeability.