Activating mutations in the ABCC8 gene in neonatal diabetes mellitus
Activating mutations in the ABCC8 gene in neonatal diabetes mellitus
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DOI：
10.1056/nejmoa055068
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发表时间：
2006-08-03
影响因子：
158.5
通讯作者：
Froguel, Philippe
中科院分区：
文献类型：
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作者：
Babenko, Andrey P.;Polak, Michel;Froguel, Philippe
背景：ATP敏感性钾通道（K（sub ATP））由β细胞蛋白磺酰脲受体（SUR 1）和内向整流钾通道亚基Kir6.2组成，是胰岛素释放的关键调节因子。它通过腺嘌呤核苷酸与Kir6.2亚基的结合而被抑制，这关闭了通道，并通过核苷酸结合或水解SUR 1而被激活，这打开了通道。这些相反作用的平衡决定了低开放通道概率P（sub 0），其控制胰腺β细胞的兴奋性。我们假设，激活突变ABCC 8，编码SUR 1，导致新生儿diabetes.METHODS：我们筛选了34例永久性或暂时性新生儿糖尿病的原因不明的ABCC 8的39个外显子。我们测定了突变型和野生型K（亚ATP）channels.Results的电生理活性：我们确定了7个错义突变9例。四个突变是家族性的，并显示与新生儿和成人发病的糖尿病垂直传播;其余的突变没有传播，也没有在300多名没有糖尿病或类似遗传背景的早发性糖尿病患者中发现。在完整的细胞和生理浓度的镁ATP突变通道有一个显着较高的P（分O）比野生型通道。这些过度活跃的通道仍然敏感的磺酰脲类药物，磺酰脲类药物的治疗导致eukaryosis.CONCLUSIONS：ABCC 8的显性突变占研究组新生儿糖尿病病例的12%。糖尿病的结果从一个新发现的机制，其中的基础镁核苷酸依赖性刺激作用的SUR 1的Kir孔是升高和封锁磺酰脲类药物被保存。
BACKGROUND:The ATP-sensitive potassium (K(sub ATP)) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, P(sub O), which controls the excitability of pancreatic beta cells. We hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes.METHODS:We screened the 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin. We assayed the electrophysiologic activity of mutant and wild-type K(sub ATP) channels.RESULTS:We identified seven missense mutations in nine patients. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remaining mutations were not transmitted and not found in more than 300 patients without diabetes or with early-onset diabetes of similar genetic background. Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had a markedly higher P(sub O) than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia.CONCLUSIONS:Dominant mutations in ABCC8 accounted for 12 percent of cases of neonatal diabetes in the study group. Diabetes results from a newly discovered mechanism whereby the basal magnesium-nucleotide-dependent stimulatory action of SUR1 on the Kir pore is elevated and blockade by sulfonylureas is preserved.