PDF(Pubmed)
Abstract：
In 2009, two groups independently linked human mutations in the inwardly rectifying K+ channel Kir4.1 (gene name KCNJ10) to a syndrome affecting the central nervous system (CNS), hearing, and renal tubular salt reabsorption. The autosomal recessive syndrome has been named EAST (epilepsy, ataxia, sensorineural deafness, and renal tubulopathy) or SeSAME syndrome (seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance), accordingly. Renal dysfunction in EAST/SeSAME patients results in loss of Na+, K+, and Mg2+ with urine, activation of the renin-angiotensin-aldosterone system, and hypokalemic metabolic alkalosis. Kir4.1 is highly expressed in affected organs: the CNS, inner ear, and kidney. In the kidney, it mostly forms heteromeric channels with Kir5.1 (KCNJ16). Biallelic loss-of-function mutations of Kir5.1 can also have disease significance, but the clinical symptoms differ substantially from those of EAST/SeSAME syndrome: although sensorineural hearing loss and hypokalemia are replicated, there is no alkalosis, but rather acidosis of variable severity; in contrast to EAST/SeSAME syndrome, the CNS is unaffected. This review provides a framework for understanding some of these differences and will guide the reader through the growing literature on Kir4.1 and Kir5.1, discussing the complex disease mechanisms and the variable expression of disease symptoms from a molecular and systems physiology perspective. Knowledge of the pathophysiology of these diseases and their multifaceted clinical spectrum is an important prerequisite for making the correct diagnosis and forms the basis for personalized therapies.
摘要：
2009年，两组独立地将向内整流K通道Kir4.1（基因名称KCNJ10）中的人类突变与影响中枢神经系统（CNS）的综合征联系起来。听力,和肾小管盐重吸收。常染色体隐性综合征被命名为EAST（癫痫，共济失调,感觉神经性耳聋,和肾小管病）或SeSAME综合征（癫痫发作，感觉神经性耳聋,共济失调,智力残疾,和电解质不平衡)，因此。EAST/SeSAME患者的肾功能障碍导致Na+的损失，K+,和尿液中的Mg2+，激活肾素-血管紧张素-醛固酮系统，和低钾血症代谢性碱中毒。Kir4.1在受影响的器官中高度表达：CNS，内耳,还有肾.在肾脏，它主要与Kir5.1(KCNJ16)形成异聚通道。Kir5.1的双等位基因功能丧失突变也可能具有疾病意义，但临床症状与EAST/SeSAME综合征的症状有很大不同：虽然感觉神经性听力损失和低钾血症被复制，没有碱中毒,而是不同严重程度的酸中毒；与EAST/SeSAME综合征相反，中枢神经系统不受影响。这篇综述为理解这些差异提供了一个框架，并将指导读者通过关于Kir4.1和Kir5.1的越来越多的文献，从分子和系统生理学的角度讨论复杂的疾病机制和疾病症状的可变表达。了解这些疾病的病理生理学及其多方面的临床谱是做出正确诊断的重要前提，并为个性化治疗奠定了基础。
