Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1
Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1
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DOI：
10.1172/jci9804
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发表时间：
2000-10-01
影响因子：
15.9
通讯作者：
Otonkoski, T
中科院分区：
文献类型：
--
作者：
Huopio, H;Reimann, F;Otonkoski, T
ATP 敏感钾通道在将代谢信号与胰腺 β 细胞中胰岛素的胞吐作用联系起来方面发挥着重要作用。这些通道由两种类型的蛋白质亚基组成：磺酰脲受体 SUR1 和内向整流钾通道 Kir6.2。编码这些蛋白质的基因突变是先天性高胰岛素血症 (CHI) 的最常见原因。自 1973 年以来，我们对芬兰 38 名 CHI 儿童患者进行了随访。我们之前报道过 SUR1 (V187D) 的功能丧失突变是导致最严重病例 CHI 的原因。我们现已在 SUR1 的第二个核苷酸结合折叠内发现了一个错义突变 E1506K，该突变在 7 名相关 CHI 患者及其母亲中发现为杂合子。所有患者均患有轻度 CHI，通常可以通过长期二氮嗪治疗来控制。这一临床发现与携带E1506K突变的重组Kir6.2和SUR1的异源共表达研究结果一致。突变的 K-ATP 通道对代谢抑制不敏感，但保留了对二氮嗪的部分反应。六名母亲中有五人患有妊娠期或永久性糖尿病，其中两人在婴儿期患有低血糖。连锁和单倍型分析支持了大谱系中的显性遗传模式。总之，我们描述了第一个显性遗传的 SUR1 突变，该突变导致生命早期的 CHI 并导致以后的胰岛素缺乏。
ATP-sensitive potassium channels play a major role in linking metabolic signals to the exocytosis of insulin in the pancreatic beta cell. These channels consist of two types of protein subunit: the sulfonylurea receptor SUR1 and the inward rectifying potassium channel Kir6.2, Mutations in the genes encoding these proteins are the most common cause of congenital hyperinsulinism (CHI). Since 1973, we have followed up 38 pediatric CHI patients in Finland. We reported previously that a loss-of-function mutation in SUR1 (V187D) is responsible for CHI of the most severe cases. We have now identified a missense mutation, E1506K, within the second nucleotide binding fold of SUR1, found heterozygous in seven related patients with CHI and in their mothers. All patients have a mild form of CHI that usually can be managed by long-term diazoxide treatment. This clinical finding is in agreement with the results of heterologous coexpression studies of recombinant Kir6.2 and SUR1 carrying the E1506K mutation. Mutant K-ATP channels were insensitive to metabolic inhibition, but a partial response to diazoxide was retained. Five of the six mothers, two of whom suffered from hypoglycemia in infancy, have developed gestational or permanent diabetes. Linkage and haplotype analysis supported a dominant pattern of inheritance in a large pedigree. In conclusion, we describe the first dominantly inherited SUR1 mutation that causes CHI in early life and predisposes to later insulin deficiency.