Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis
Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis
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DOI：
10.1073/pnas.1221400110
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发表时间：
2013-03-19
影响因子：
11.1
通讯作者：
Patapoutian, Ardem
中科院分区：
文献类型：
--
作者：
Coste, Bertrand;Houge, Gunnar;Patapoutian, Ardem
机械转导是将机械力转化为生物信号的途径，在生理学中扮演着重要的角色，但尚未被充分描述。最近发现的广泛表达的、机械激活的离子通道被假设在哺乳动物的机械转导中发挥作用。在这里，我们描述了远端关节挛缩5型亚型患者的两种不同的PIEZO2突变，其特征是广泛性常染色体显性挛缩伴眼球运动受限，限制性肺部疾病和膝关节交叉韧带的变异性缺失。电生理研究表明，两个PIEZO2突变会影响与通道失活相关的生物物理特性：E2727del和I802F突变都会导致依赖PIEZO2的机械激活电流从失活中恢复得更快，而E2727del也会导致失活减慢。两种类型的动力学变化都会导致响应给定机械刺激的通道活性增加，这表明5型远端关节挛缩可能是由PIEZO2的功能获得突变引起的。我们进一步表明，突变的PIEZO2 cdna的过表达不会引起细胞的组成活性或毒性，表明观察到的表型可能是由于机械转导缺陷。我们的研究确定了一种通道病，并将机械激活离子通道的功能障碍与发育畸形和关节挛缩联系起来。
cMechanotransduction, the pathway by which mechanical forces are translated to biological signals, plays important but poorly characterized roles in physiology. PIEZOs are recently identified, widely expressed, mechanically activated ion channels that are hypothesized to play a role in mechanotransduction in mammals. Here, we describe two distinct PIEZO2 mutations in patients with a subtype of Distal Arthrogryposis Type 5 characterized by generalized autosomal dominant contractures with limited eye movements, restrictive lung disease, and variable absence of cruciate knee ligaments. Electrophysiological studies reveal that the two PIEZO2 mutations affect biophysical properties related to channel inactivation: both E2727del and I802F mutations cause the PIEZO2-dependent, mechanically activated currents to recover faster from inactivation, while E2727del also causes a slowing of inactivation. Both types of changes in kinetics result in increased channel activity in response to a given mechanical stimulus, suggesting that Distal Arthrogryposis Type 5 can be caused by gain-of-function mutations in PIEZO2. We further show that overexpression of mutated PIEZO2 cDNAs does not cause constitutive activity or toxicity to cells, indicating that the observed phenotype is likely due to a mechanotransduction defect. Our studies identify a type of channelopathy and link the dysfunction of mechanically activated ion channels to developmental malformations and joint contractures.