Sulfonylurea-Insensitive Permanent Neonatal Diabetes Caused by a Severe Gain-of-Function Tyr330His Substitution in Kir6.2.
Sulfonylurea-Insensitive Permanent Neonatal Diabetes Caused by a Severe Gain-of-Function Tyr330His Substitution in Kir6.2.
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DOI：
10.1159/000521858
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发表时间：
2022
影响因子：
3.2
通讯作者：
中科院分区：
文献类型：
--
作者：
编码胰腺和神经元KATP通道Kir6.2亚基的基因KCNJ11的突变与一系列新生儿糖尿病疾病有关。变异筛选用于确定新生儿糖尿病的病因，持续血糖监测用于评估磺脲类药物治疗的有效性。通过电生理分析变异KATP通道功能，确定分子基础。我们在一名被诊断为磺脲类药物耐药的永久性新生儿糖尿病和发育迟缓（iDEND）的意大利儿童中发现了一种以前未被表征的KCNJ11突变C . 988t >C [pTyr330His]。重组KATP通道的功能分析表明，由于atp抑制的减少，这种突变导致了剧烈的功能获得。此外，我们证明Tyr330His取代导致对磺酰脲、格列本脲的敏感性显著降低。在本课题中，KCNJ11(c)。988t> C)突变引起新生儿糖尿病，伴轻度发育迟缓，对磺脲类药物纠正不敏感。这可以解释为Tyr330His取代所导致的磺脲敏感性的分子丧失，并强调了对此类突变进行分子分析的必要性。
Mutations in KCNJ11, the gene encoding the Kir6.2 subunit of pancreatic and neuronal KATP channels, are associated with a spectrum of neonatal diabetes diseases. Variant screening was used to identify cause of neonatal diabetes, and continuous glucose monitoring used to assess effectiveness of sulfonylurea treatment. Electrophysiological analysis of variant KATP channel function was used to determine molecular basis. We identified a previously uncharacterized KCNJ11 mutation, c.988T>C [pTyr330His], in an Italian child diagnosed with sulfonylurea-resistant permanent neonatal diabetes and developmental delay (iDEND). Functional analysis of recombinant KATP channels reveals that this mutation causes a drastic gain-of-function, due to a reduction in ATP-inhibition. Further, we demonstrate that the Tyr330His substitution causes a significant decrease in sensitivity to the sulfonylurea, glibenclamide. In this subject, the KCNJ11(c.988T>C) mutation provoked neonatal diabetes, with mild developmental delay, which was insensitive to correction by sulfonylurea therapy. This is explained by the molecular loss of sulfonylurea sensitivity conferred by the Tyr330His substitution, and highlights the need for molecular analysis of such mutations.
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影响因子：
16.2
作者：
Bowman P;Mathews F;Barbetti F;Shepherd MH;Sanchez J;Piccini B;Beltrand J;Letourneau-Freiberg LR;Polak M;Greeley SAW;Rawlins E;Babiker T;Thomas NJ;De Franco E;Ellard S;Flanagan SE;Hattersley AT;Neonatal Diabetes International Collaborative Group
通讯作者：
Neonatal Diabetes International Collaborative Group
影响因子：
4.8
作者：
Babenko, AP;Bryan, J
通讯作者：
Bryan, J
影响因子：
7.7
作者：
Masia, Ricard;De Leon, Diva D.;Nichols, Colin G.
通讯作者：
Nichols, Colin G.
影响因子：
7.7
作者：
Shimomura, Kenju;Girard, Christophe A. J.;Ashcroft, Frances M.
通讯作者：
Ashcroft, Frances M.
DOI：
10.1111/j.1365-2125.1990.tb03688.x
发表时间：
1990-06-01
影响因子：
3.4
作者：
COPPACK, SW;LANT, AF;RODGERS, AV
通讯作者：
RODGERS, AV