'Gardos Channelopathy': a variant of hereditary Stomatocytosis with complex molecular regulation
'Gardos Channelopathy': a variant of hereditary Stomatocytosis with complex molecular regulation
复制标题
DOI：
10.1038/s41598-017-01591-w
复制
发表时间：
2017-05-11
影响因子：
4.6
通讯作者：
Bianchi, Paola
中科院分区：
文献类型：
--
作者：
Fermo, Elisa;Bogdanova, Anna;Bianchi, Paola
Gardos通道是存在于包括RBC在内的几种组织中的Ca 2+敏感性、K+选择性通道，其中它参与细胞体积调节。最近，在两个不同的氨基酸残基突变KCNN 4已报告在遗传性干细胞症患者。我们通过全外显子组测序确定了一个新的家族，其中两名成员患有慢性溶血性贫血，携带KCNN 4基因突变R352 H。未检测到编码RBC细胞骨架、膜或通道蛋白的基因的其他突变。我们对患者的红细胞进行了功能研究，以评估R352 H突变对细胞特性并最终对临床表型的影响。Gardos通道超活化在循环红细胞和从外周CD 34+细胞离体分化的成红细胞中得到证实。观察到多种离子转运系统功能的病理改变，表明存在补偿效应，最终防止患者红细胞中的细胞脱水;此外，流式细胞术和共聚焦荧光活细胞成像显示两名患者红细胞中的Ca 2+过载和红细胞对肿胀的Ca 2+摄取超敏反应。总之，这些研究结果表明，“Gardos通道病”是一个复杂的病理，在某种程度上不同于常见的遗传性干细胞症。
The Gardos channel is a Ca2+ sensitive, K+ selective channel present in several tissues including RBCs, where it is involved in cell volume regulation. Recently, mutations at two different aminoacid residues in KCNN4 have been reported in patients with hereditary xerocytosis. We identified by whole exome sequencing a new family with two members affected by chronic hemolytic anemia carrying mutation R352H in the KCNN4 gene. No additional mutations in genes encoding for RBCs cytoskeletal, membrane or channel proteins were detected. We performed functional studies on patients' RBCs to evaluate the effects of R352H mutation on the cellular properties and eventually on the clinical phenotype. Gardos channel hyperactivation was demonstrated in circulating erythrocytes and erythroblasts differentiated ex-vivo from peripheral CD34+ cells. Pathological alterations in the function of multiple ion transport systems were observed, suggesting the presence of compensatory effects ultimately preventing cellular dehydration in patient's RBCs; moreover, flow cytometry and confocal fluorescence live-cell imaging showed Ca2+ overload in the RBCs of both patients and hypersensitivity of Ca2+ uptake by RBCs to swelling. Altogether these findings suggest that the 'Gardos channelopathy' is a complex pathology, to some extent different from the common hereditary xerocytosis.