KCNJ10 Mutations Disrupt Function in Patients with EAST Syndrome
KCNJ10 Mutations Disrupt Function in Patients with EAST Syndrome
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DOI：
10.1159/000330250
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发表时间：
2011-01-01
影响因子：
--
通讯作者：
Zdebik, Anselm A.
中科院分区：
文献类型：
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作者：
Freudenthal, Bernard;Kulaveerasingam, Duvaraka;Zdebik, Anselm A.
背景/目的：内向整流性K+通道KCNJ10/Kir4.1突变导致一种常染色体隐性遗传病，其特征为癫痫、共济失调、感音神经性耳聋和小管病变(East综合征)。KCNJ10在肾脏远端曲管、耳蜗纹和脑胶质细胞中有表达。对临床诊断为EAST综合征的患者进行基因分型，以鉴定和研究KCNJ10的突变。方法：对患者DNA进行测序，确定新的突变。克隆了突变型和野生型KCNJ10结构，并在非洲爪哇卵母细胞中异源表达。采用双电极电压钳技术测定全细胞钾电流。结果：发现了3个新的KCNJ10突变(p.R65C、p.F75L和p.V259fs259X)，并且发现了一个纯合子状态的突变p.R297C。野生型表达KCNJ10的卵母细胞表现出强烈的内向整流电流，相比之下，所有突变体的内向整流电流都显著减少(p<；0.001)。Ba2+对KCNJ10电流的特异性抑制作用在除V259X外的所有突变型通道中均有残留作用(p<；0.05)。结论：KCNJ10基因突变可导致EAST综合征，KCNJ10基因突变导致K+电导显著降低。任何肾脏Gitelman样表型伴其他神经体征和症状如共济失调、癫痫或感音神经性耳聋的患者应考虑EAST综合征。版权所有(C)2011 S.Karger AG，巴塞尔
Background/Aims: Mutations in the inwardly-rectifying K+ channel KCNJ10/Kir4.1 cause an autosomal recessive disorder characterized by epilepsy, ataxia, sensorineural deafness and tubulopathy (EAST syndrome). KCNJ10 is expressed in the kidney distal convoluted tubule, cochlear stria vascularis and brain glial cells. Patients clinically diagnosed with EAST syndrome were genotyped to identify and study mutations in KCNJ10. Methods: Patient DNA was sequenced and new mutations identified. Mutant and wild-type KCNJ10 constructs were cloned and heterologously expressed in Xenopus oocytes. Whole-cell K+ currents were measured by two-electrode voltage clamping. Results: Three new mutations in KCNJ10 (p.R65C, p.F75L and p.V259fs259X) were identified, and mutation p.R297C, previously only seen in a compound heterozygous patient, was found in a homozygous state. Wild-type human KCNJ10-expressing oocytes showed strongly inwardly-rectified currents, which by comparison were significantly reduced in all the mutants (p < 0.001). Specific inhibition of KCNJ10 currents by Ba2+ demonstrated residual function in all mutant channels (p < 0.05) but V259X. Conclusion: This study confirms that EAST syndrome can be caused by many different mutations in KCNJ10 that significantly reduce K+ conductance. EAST syndrome should be considered in any patient with a renal Gitelman-like phenotype with additional neurological signs and symptoms like ataxia, epilepsy or sensorineural deafness. Copyright (C) 2011 S. Karger AG, Basel