The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy
The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy
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DOI：
10.1210/jc.2007-1826
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发表时间：
2008-03-01
影响因子：
5.8
通讯作者：
Barbetti, Fabrizio
中科院分区：
文献类型：
--
作者：
Koster, Joseph C.;Cadario, Francesco;Barbetti, Fabrizio
背景：atp敏感钾通道（KATP） Kir6.2亚基（KCNJ11）突变是新生儿糖尿病的基础。在严重的情况下，Kir6.2突变会导致发育迟缓、癫痫和新生儿糖尿病（DEND）。所有检测到的Kir6.2突变都降低了ATP对KATP的抑制，这被预测会抑制神经元（外周和中枢）、肌肉和胰腺的电活动。抑制性磺脲类药物（SUs）已成功用于治疗Kir6.2突变激活患者的糖尿病。有两篇关于su治疗的DEND患者神经功能改善的报道，但没有关于成年期改善的报道。目的：该研究的目的是确定27岁KCNJ11突变（G53D）患者中间DEND的分子基础以及患者对SU治疗的反应。设计：G53D患者在160 d的时间内从胰岛素转移到格列齐特，然后转移到格列本脲。在整个过程中评估运动功能。电生理学评估了G53D突变对K-ATP活性的影响。结果：G53D患者在SU治疗后血糖控制和运动协调得到改善，尽管格列本脲比格列齐特更有效。重组的G53D通道表现出ATP敏感性降低，预计这将抑制体内的电活动。与SUR1（胰腺和神经元亚型）共表达的G53D通道被格列齐特高亲和力阻断，但与SUR2A（骨骼肌亚型）共表达时对阻断不敏感。格列本脲在与SUR1或SUR2A共表达的G53D通道中存在高亲和力阻滞。结论：结果表明，SUs可以解决成人中度DEND的运动功能障碍，这种改善是由于抑制神经元而不是骨骼肌K-ATP。
Context: Mutations in the Kir6.2 subunit (KCNJ11) of the ATP-sensitive potassium channel (KATP) underlie neonatal diabetes mellitus. In severe cases, Kir6.2 mutations underlie developmental delay, epilepsy, and neonatal diabetes (DEND). All Kir6.2 mutations examined decrease the ATP inhibition of KATP, which is predicted to suppress electrical activity in neurons (peripheral and central), muscle, and pancreas. Inhibitory sulfonylureas (SUs) have been used successfully to treat diabetes in patients with activating Kir6.2 mutations. There are two reports of improved neurological features in SU-treated DEND patients but no report of such improvement in adulthood.Objective: The objective of the study was to determine the molecular basis of intermediate DEND in a 27-yr-old patient with a KCNJ11 mutation (G53D) and the patient's response to SU therapy.Design: The G53D patient was transferred from insulin to gliclazide and then to glibenclamide over a 160-d period. Motor function was assessed throughout. Electrophysiology assessed the effect of the G53D mutation on K-ATP activity.Results: The G53D patient demonstrated improved glycemic control and motor coordination with SU treatment, although glibenclamide was more effective than gliclazide. Reconstituted G53D channels exhibit reduced ATP sensitivity, which is predicted to suppress electrical activity in vivo. G53D channels coexpressed with SUR1 (the pancreatic and neuronal isoform) exhibit high-affinity block by gliclazide but are insensitive to block when coexpressed with SUR2A (the skeletal muscle isoform). High-affinity block by glibenclamide is present in G53D channels coexpressed with either SUR1 or SUR2A.Conclusion: The results demonstrate that SUs can resolve motor dysfunction in an adult with intermediate DEND and that this improvement is due to inhibition of the neuronal but not skeletal muscle K-ATP.