KCNJ10 encodes the inward-rectifying potassium channel (Kir4.1) that is expressed in the brain, inner ear, and kidney. Loss-of-function mutations in KCNJ10 gene cause a complex syndrome consisting of epilepsy, ataxia, intellectual disability, sensorineural deafness, and tubulopathy (EAST/SeSAME syndrome). Patients with EAST/SeSAME syndrome display renal salt wasting and electrolyte imbalance that resemble the clinical features of impaired distal tubular salt transport in Gitelman’s syndrome. A key distinguishing feature between these two conditions is the additional neurological (extrarenal) manifestations found in EAST/SeSAME syndrome. Recent reports have further expanded the clinical and mutational spectrum of KCNJ10-related disorders including non-syndromic early-onset cerebellar ataxia. Here, we describe a kindred of three affected siblings with early-onset ataxia, deafness, and progressive spasticity without other prominent clinical features. By using targeted next-generation sequencing, we have identified two novel missense variants, c.488G>A (p.G163D) and c.512G>A (p.R171Q), in the KCNJ10 gene that, in compound heterozygosis, cause this distinctive EAST/SeSAME phenotype in our family. Electrophysiological characterization of these two variants confirmed their pathogenicity. When expressed in CHO cells, the R171Q mutation resulted in 50% reduction of currents compared to wild-type KCNJ10 and G163D showed a complete loss of function. Co-expression of G163D and R171Q had a more pronounced effect on currents and membrane potential than R171Q alone but less severe than single expression of G163D. Moreover, the effect of the mutations seemed less pronounced in the presence of Kir5.1 (encoded by KCNJ16), with whom the renal Kir4.1 channels form heteromers. This partial functional rescue by co-expression with Kir5.1 might explain the lack of renal symptoms in the patients. This report illustrates that a spectrum of disorders with distinct clinical symptoms may result from mutations in different parts of KCNJ10, a gene initially associated only with the EAST/SeSAME syndrome.

中文翻译：

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KCNJ10基因的新型突变与独特的共济失调，感觉神经性听力损失和痉挛性临床表型有关。

KCNJ10编码在大脑，内耳和肾脏中表达的内向整流钾通道（Kir4.1）。KCNJ10基因的功能丧失突变导致复杂的综合征，包括癫痫，共济失调，智力障碍，感音神经性耳聋和肾小管病（EAST / SeSAME综合征）。EAST / SeSAME综合征患者表现出肾脏盐消耗和电解质失衡，类似于吉特曼综合征中远端肾小管盐转运受损的临床特征。这两种情况之间的主要区别特征是在EAST / SeSAME综合征中发现的其他神经系统（肾外）表现。最近的报道进一步扩大了KCNJ10的临床和突变谱相关疾病，包括非综合征性早发性小脑共济失调。在这里，我们描述了一个由三个受影响的兄弟姐妹组成的家族，它们具有早发共济失调，耳聋和进行性痉挛，而没有其他突出的临床特征。通过使用靶向的下一代测序，我们在KCNJ10中鉴定了两个新的错义变体c.488G> A（p.G163D）和c.512G> A（p.R171Q）在我们的家庭中，这种基因在复合杂合中会导致这种独特的EAST / SeSAME表型。这两个变体的电生理学特征证实了它们的致病性。当在CHO细胞中表达时，与野生型KCNJ10和G163D相比，R171Q突变导致电流减少50％，G163D显示功能完全丧失。与单独的R171Q相比，G163D和R171Q的共表达对电流和膜电位的影响更明显，但不如单个表达的G163D严重。此外，在存在Kir5.1（由KCNJ16编码）的情况下，突变的影响似乎不太明显），与它们的肾脏Kir4.1通道形成异聚体。通过与Kir5.1共表达进行部分功能性抢救可能可以解释患者缺乏肾脏症状。该报告表明，一系列具有独特临床症状的疾病可能是由KCNJ10不同部分的突变引起的，该基因最初仅与EAST / SeSAME综合征相关。