Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels.
Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels.
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DOI：
10.1038/ncomms2899
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发表时间：
2013
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
遗传性脱水型口腔细胞增多症(DHS)是一种具有红细胞膜特性缺陷的遗传性疾病，可导致细胞内阳离子浓度失衡。最近，机械激活的PIEZO1(FAM38A)离子通道中的两个错义突变被认为与DHS有关。然而，目前尚不清楚这些突变是如何影响PIEZO1功能的。在这里，我们通过连锁分析和一个大家系的全外显子测序，以及在另外两个家系和11个无关的DHS病例中的Sanger测序，我们发现了PIEZO1的三个新的错义突变和一个重复的重复，证明它是DHS的主要基因。所有与DHS相关的突变都位于PIEZO1的C-末端一半。值得注意的是，我们发现所有PIEZO1突变都会引起机械激活电流，而机械激活电流的失活速度比野生型电流慢。这种功能增强的PIEZO1表型提供了洞察力，有助于解释DHS患者红细胞阳离子渗透性增加的原因。我们的发现也提示了机械转导在红细胞生物学和病理生理学中的新作用。
Dehydrated hereditary stomatocytosis (DHS) is a genetic condition with defective red blood cell (RBC) membrane properties that causes an imbalance in intracellular cation concentrations. Recently, two missense mutations inthe mechanically activated PIEZO1(FAM38A) ion channel were associated with DHS. However, it is not known how these mutations affect PIEZO1 function. Here, by combining linkage analysis and whole-exome sequencing in a large pedigree and Sanger sequencing in two additional kindreds and 11 unrelated DHS cases, we identifythree novel missense mutations and one recurrent duplication in PIEZO1, demonstrating that it is the major gene for DHS. All the DHS-associated mutations locate at C-terminal half of PIEZO1. Remarkably, we find that all PIEZO1 mutations give rise to mechanically activated currents that inactivate more slowly than wild-type currents. This gain-of-function PIEZO1 phenotype provides insight that helps to explain the increased permeability of cations in RBCs of DHS patients. Our findings also suggest a new role for mechanotransduction in RBC biology and pathophysiology.
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影响因子：
9.8
作者：
Carella, M;Stewart, G;Iolascon, A
通讯作者：
Iolascon, A
DOI：
10.4161/chan.21050
发表时间：
2012-07
期刊：
Channels (Austin, Tex.)
影响因子：
--
作者：
Gottlieb PA;Sachs F
通讯作者：
Sachs F
影响因子：
12.8
作者：
Andolfo, Immacolata;Alper, Seth L.;Iolascon, Achille
通讯作者：
Iolascon, Achille
影响因子：
20.3
作者：
Bruce, Lesley J.;Guizouarn, Helene;Stewart, Gordon W.
通讯作者：
Stewart, Gordon W.
影响因子：
3.1
作者：
Beaurain, Genevieve;Mathieu, Flavie;Jeunemaitre, Xavier
通讯作者：
Jeunemaitre, Xavier