Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis)
Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis)
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DOI：
10.1002/ajh.24117
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发表时间：
2015-10-01
影响因子：
12.8
通讯作者：
Iolascon, Achille
中科院分区：
文献类型：
--
作者：
Andolfo, Immacolata;Russo, Roberta;Iolascon, Achille
脱水遗传性口细胞增多症（DHSt）是一种常染色体显性遗传的先天性溶血性贫血，伴有中度脾肿大和代偿性溶血。受影响的红细胞的特征是红细胞膜的非特异性阳离子泄漏，反映在钠含量升高、钾含量降低、MCHC和MCV升高以及渗透脆性降低。迄今为止报道的大多数有症状的DHSt病例与机械敏感性阳离子通道基因PIEZO 1的功能获得性突变相关。最近的一项研究已经确定了两个DHSt家族与编码Gardos通道（KCa3.1）的KCNN4基因中的单个突变相关，Gardos通道是红系Ca 2+敏感的K+通道，具有中等电导，也在许多其他细胞类型中表达。我们在这里，在第二次报告DHSt与KCNN4突变，两个以前未确诊的DHSt家庭。NA家族表现出与最近描述的相同的从头错义突变，表明DHSt突变的热点密码子。WO家族在通道的离子转运结构域中携带一种新的遗传性错义突变。患者的轻度溶血性贫血在脾切除术后没有改善，但脾切除术没有导致严重的血栓栓塞事件。我们进一步表征了KCNN4在突变患者中以及在CD34+细胞和K562细胞的红系分化期间的表达。我们还分析了KCNN4在小鼠胚胎发育过程中的表达。(C)2015 Wiley Periodicals，Inc.
Dehydrated hereditary stomatocytosis (DHSt) is an autosomal dominant congenital hemolytic anemia with moderate splenomegaly and often compensated hemolysis. Affected red cells are characterized by a nonspecific cation leak of the red cell membrane, reflected in elevated sodium content, decreased potassium content, elevated MCHC and MCV, and decreased osmotic fragility. The majority of symptomatic DHSt cases reported to date have been associated with gain-of-function mutations in the mechanosensitive cation channel gene, PIEZO1. A recent study has identified two families with DHSt associated with a single mutation in the KCNN4 gene encoding the Gardos channel (KCa3.1), the erythroid Ca2+-sensitive K+ channel of intermediate conductance, also expressed in many other cell types. We present here, in the second report of DHSt associated with KCNN4 mutations, two previously undiagnosed DHSt families. Family NA exhibited the same de novo missense mutation as that recently described, suggesting a hot spot codon for DHSt mutations. Family WO carried a novel, inherited missense mutation in the ion transport domain of the channel. The patients' mild hemolytic anemia did not improve post-splenectomy, but splenectomy led to no serious thromboembolic events. We further characterized the expression of KCNN4 in the mutated patients and during erythroid differentiation of CD34+ cells and K562 cells. We also analyzed KCNN4 expression during mouse embryonic development. (C) 2015 Wiley Periodicals, Inc.