Departments of Genetics and Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street, New Haven, CT, 06510, USA.
Department of Pediatrics, SUNY Upstate Medical University, 750 E. Adams St., Syracuse, NY, 13210, USA.
Pediatr Nephrol. 2012 Nov;27(11):2081-2090. doi: 10.1007/s00467-012-2219-4. Epub 2012 Aug 21.
Mutations in the K(+) channel KCNJ10 (Kir4.1) cause an autosomal recessive syndrome featuring seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME). Kir4.1 localizes to the basolateral membrane of the renal distal convoluted tubule, and its loss of function mimics renal features of Gitelman syndrome, with hypokalemic alkalosis, hypomagnesemia, and hypocalciuria. Presentation early in life due to seizures provides an opportunity to investigate the development of the electrolyte defect with age.
We used DNA sequencing, electrophysiology, confocal imaging, and biochemistry to identify a new KCNJ10 mutation in a previously unreported family and determine its impact on channel function. We examined medical records to follow the development of electrolyte disorders with age.
The four affected members were all homozygous for a novel T57I mutation that confers biochemical loss-of-function. Electrolytes in affected children were normal in the first years of life but showed significant worsening with age, resulting in clinically significant defects at age 5-8 years. Similar findings were seen in other SeSAME patients.
These findings provide evidence for a delayed activity of salt reabsorption by the distal convoluted tubule and suggest an explanation for the delayed clinical presentation of subjects with Gitelman syndrome.
K(+) 通道 KCNJ10（Kir4.1）的突变导致常染色体隐性遗传综合征，其特征为癫痫发作、感觉神经性耳聋、共济失调、智力迟钝和电解质失衡（SeSAME）。Kir4.1 定位于肾远曲小管的基底外侧膜，其功能丧失类似于 Gitelman 综合征的肾脏特征，表现为低钾性碱中毒、低镁血症和低钙尿症。由于癫痫发作导致早期发病，为研究年龄相关电解质缺陷的发展提供了机会。
我们使用 DNA 测序、电生理学、共聚焦成像和生物化学方法在一个以前未报道的家族中鉴定了一种新的 KCNJ10 突变，并确定了其对通道功能的影响。我们查阅了病历以随年龄观察电解质紊乱的发展情况。
四个受影响的成员均为新型 T57I 突变的纯合子，该突变导致生化功能丧失。受影响儿童的电解质在生命的头几年是正常的，但随着年龄的增长明显恶化，导致 5-8 岁时出现临床显著缺陷。其他 SeSAME 患者也有类似发现。
这些发现为远曲小管盐重吸收的延迟活性提供了证据，并为 Gitelman 综合征患者的延迟临床表现提供了一种解释。
