Dominant-Negative Effect of a Missense Variant in the TASK-2 (KCNK5) K+ Channel Associated with Balkan Endemic Nephropathy.
Dominant-Negative Effect of a Missense Variant in the TASK-2 (KCNK5) K+ Channel Associated with Balkan Endemic Nephropathy.
复制标题
DOI：
10.1371/journal.pone.0156456
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Tucker SJ
中科院分区：
文献类型：
--
作者：
Reed AP;Bucci G;Abd-Wahab F;Tucker SJ
ASK-2是K+通道的双孔结构域（K2 P）亚家族的成员，由KCNK 5基因编码。该通道主要在肾上皮组织中表达，并且最近已显示KCNK 5中的潜在有害错义变体在易于发展为巴尔干半岛的地方性肾病（BEN）（一种病因不明的慢性肾小管间质性肾病）的患者中流行。在这项研究中，我们表明，这种变体（T108 P）导致通道功能的完全丧失，并与细胞表面的ASK-2通道亚基的主要减少有关。此外，当与野生型亚基共表达时，这些突变亚基对通道功能具有抑制性或“显性负”效应。这种错义变体位于M2跨膜螺旋的细胞外表面，并且通过使用结构建模和进一步功能分析的组合，我们还表明这种高度保守的苏氨酸残基对于其他K2 P通道的正确功能至关重要。因此，这些结果提供了进一步的结构和功能的见解，这种错义变异体的可能的病理生理作用的任务-2。
TASK-2, a member of the Two-Pore Domain (K2P) subfamily of K+ channels, is encoded by the KCNK5 gene. The channel is expressed primarily in renal epithelial tissues and a potentially deleterious missense variant in KCNK5 has recently been shown to be prevalent amongst patients predisposed to the development of Balkan Endemic Nephropathy (BEN), a chronic tubulointerstitial renal disease of unknown etiology. In this study we show that this variant (T108P) results in a complete loss of channel function and is associated with a major reduction in TASK-2 channel subunits at the cell surface. Furthermore, these mutant subunits have a suppressive or ‘dominant-negative’ effect on channel function when coexpressed with wild-type subunits. This missense variant is located at the extracellular surface of the M2 transmembrane helix and by using a combination of structural modelling and further functional analysis we also show that this highly-conserved threonine residue is critical for the correct function of other K2P channels. These results therefore provide further structural and functional insights into the possible pathophysiological effects of this missense variant in TASK-2.