Altered electroretinograms in patients with KCNJ10 mutations and EAST syndrome
Altered electroretinograms in patients with KCNJ10 mutations and EAST syndrome
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DOI：
10.1113/jphysiol.2010.198531
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发表时间：
2011-04-01
影响因子：
5.5
通讯作者：
Bockenhauer, Detlef
中科院分区：
文献类型：
--
作者：
Thompson, Dorothy A.;Feather, Sally;Bockenhauer, Detlef
非技术概述光刺激离子流通过视网膜。这在角膜处产生电位变化，其被记录为视网膜电图（ERG）。我们对钾离子在产生ERG中的作用的理解是基于动物模型。KCJN 10基因构成Kir4.1，视网膜Muller细胞上表达的主要钾通道。我们已经能够通过记录具有已知KCJN 10突变的EAST综合征患者的ERG来首次研究这种钾通道对人类视网膜的影响。我们的数据表明，减少的振幅明视负响应的光适应的ERG和暗适应的ERG的灵敏度下降。这些数据增加了我们对ERG如何产生以及为什么这些ERG参数可能在疾病中受到影响的理解。KCNJ 10基因（Kir4.1）表达的K+通道先前已在动物实验中证明在视网膜功能中的重要性。最近，KCNJ 10的突变被认为是人类的致病性，引起一系列症状，包括癫痫、共济失调、感觉神经性耳聋和称为EAST综合征的肾小管病变。我们研究了KCNJ 10突变对4例EAST综合征患者的视网膜电图（ERG）的影响。闪光强度为0.001-10 phot cd s/m2，暗点闪光强度为0.3-10 phot cd s/m2，暗点闪光强度为0.001-10 phot cd s/m2。所有患者光适应视网膜的ERG波形均显示明视负反应（PhNR）振幅降低（P < 0.001）。明视ERG显示出b波到达峰值的时间延迟，但明视丘（即到达峰值的时间和振幅随亮度闪光强度的相对变化）得以保留。闪光强度为0.01至0.1 phot cd s/m2的暗视ERG显示，与对照组相比，2例患者的b波发作前延迟长达20 ms。刺激-反应函数用Michaelis-Menten方程拟合，两例患者的视网膜敏感性明显低于对照组（P < 0.001）。我们的研究首次在人类ERG中显示了与影响Muller细胞K+通道的KCNJ 10突变相关的变化。这些数据说明了KCNJ 10功能在近端以及可能还有远端人类视网膜生理学中的作用。
Non-technical summaryLight stimulates ion flow through the retina. This generates a potential change at the cornea which is recorded as an electroretinogram (ERG). Our understanding of the role of potassium ions in generating the ERG is based on animal models. The KCJN10 gene constitutes Kir4.1, the principle potassium channel expressed on the retinal Muller cell. We have been able to study the impact of this potassium channel on the human retina for the first time by recording the ERGs of patients with EAST syndrome who have known mutations of KCJN10. Our data show a reduction in the amplitude of the photopic negative response of the light-adapted ERG and a decrease in the sensitivity of the dark-adapted ERG. These data increase our understanding of how the ERG is generated and why these ERG parameters may be affected in disease.The K+ channel expressed by the KCNJ10 gene (Kir4.1) has previously demonstrated importance in retinal function in animal experiments. Recently, mutations in KCNJ10 were recognised as pathogenic in man, causing a constellation of symptoms, including epilepsy, ataxia, sensorineural deafness and a renal tubulopathy designated as EAST syndrome. We have studied the impact of KCNJ10 mutations on the human electroretinogram (ERG) in four unrelated patients with EAST syndrome. Corneal ganzfeld ERGs were elicited in response to flash stimuli of strengths of 0.001-10 phot cd s/m2 presented scotopically, and 0.3-10 phot cd s/m2 presented photopically. ERG waveforms from light-adapted retinae of all patients showed reduced amplitudes of the photopic negative response (PhNR) (P < 0.001). The photopic ERGs showed a delay in b-wave time to peak, but the photopic hill, i.e. the relative variation of time to peak and amplitude with luminance flash strength, was preserved. Scotopic ERGs to flash strengths 0.01 to 0.1 phot cd s/m2 showed a delay of up to 20 ms before the onset of the b-wave in two patients compared to controls. Stimulus-response functions were fitted by Michaelis-Menten equations and showed significantly lower retinal sensitivity in two patients than in controls (P < 0.001). Our study for the first time in the human ERG shows changes in association with KCNJ10 mutations affecting a Muller cell K+ channel. These data illustrate the role of KCNJ10 function in the physiology of proximal and possibly also the distal human retina.