A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes
A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes
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DOI：
10.1093/hmg/ddl101
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发表时间：
2006-06-01
影响因子：
3.5
通讯作者：
Ellard, Sian
中科院分区：
文献类型：
--
作者：
Proks, Peter;Arnold, Amanda L.;Ellard, Sian
新生儿糖尿病是一种遗传异质性疾病，有9种不同的遗传病因。编码Kir6.2的KCNJ11基因杂合激活突变是永久性新生儿糖尿病最常见的原因，Kir6.2是atp敏感钾（K-ATP）通道的成孔亚基。磺酰脲受体（SUR1）是胰腺β细胞K-ATP通道的调控亚基。因此，我们假设编码SUR1的ABCC8基因的激活突变可能导致新生儿糖尿病。我们在一名患有严重发育迟缓、癫痫和新生儿糖尿病（DEND综合征）的患者的ABCC8基因中发现了一个新的杂合突变F132L。这种突变是从头出现的，在150条对照染色体中不存在。残基F132显示出跨物种的进化保守性，它位于SUR1的第一组跨膜螺旋（TMD0）上，被认为与Kir6.2相互作用。重组K-ATP通道的功能研究表明，F132L显著降低了K-ATP通道对MgATP抑制的敏感性，从而增加了全细胞K-ATP电流。这种ABCC8突变的功能后果反映了导致新生儿糖尿病的KCNJ11突变，并为Kir6.2和SUR1的相互作用提供了新的见解。由于SUR1在神经元和β细胞中表达，这种突变可以解释新生儿糖尿病和神经表型。我们的研究结果表明，SUR1突变构成了新生儿糖尿病的一种新的遗传病因，并通过降低K-ATP通道的ATP敏感性起作用。
Neonatal diabetes is a genetically heterogeneous disorder with nine different genetic aetiologies reported to date. Heterozygous activating mutations in the KCNJ11 gene encoding Kir6.2, the pore-forming subunit of the ATP-sensitive potassium (K-ATP) channel, are the most common cause of permanent neonatal diabetes. The sulphonylurea receptor (SUR) SUR1 serves as the regulatory subunit of the K-ATP channel in pancreatic beta cells. We therefore hypothesized that activating mutations in the ABCC8 gene, which encodes SUR1, might cause neonatal diabetes. We identified a novel heterozygous mutation, F132L, in the ABCC8 gene of a patient with severe developmental delay, epilepsy and neonatal diabetes (DEND syndrome). This mutation had arisen de novo and was not present in 150 control chromosomes. Residue F132 shows evolutionary conservation across species and is located in the first set of transmembrane helices (TMD0) of SUR1, which is proposed to interact with Kir6.2. Functional studies of recombinant K-ATP channels demonstrated that F132L markedly reduces the sensitivity of the K-ATP channel to inhibition by MgATP and this increases the whole-cell K-ATP current. The functional consequence of this ABCC8 mutation mirrors that of KCNJ11 mutations causing neonatal diabetes and provides new insights into the interaction of Kir6.2 and SUR1. As SUR1 is expressed in neurones as well as in beta cells, this mutation can account for both neonatal diabetes and the neurological phenotype. Our results demonstrate that SUR1 mutations constitute a new genetic aetiology for neonatal diabetes and that they act by reducing the K-ATP channel's ATP sensitivity.