Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations
Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations
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DOI：
10.1172/jci35414
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发表时间：
2008-08-01
影响因子：
15.9
通讯作者：
Stanley, Charles A.
中科院分区：
文献类型：
--
作者：
Pinney, Sara E.;MacMullen, Courtney;Stanley, Charles A.
先天性高胰岛素血症是一种胰岛素分泌失调的病症，通常由胰腺P细胞中ATP敏感性K+（K-ATP）通道的失活突变引起。虽然编码K-ATP亚基的两个基因ABCC 8（SUR1）和KCNJ11（Kir6.2）的大多数致病突变是隐性遗传的，但也有一些显性遗传失活突变的报道。为了更好地了解显性和隐性遗传失活K-ATP突变之间的差异，我们确定并表征了16个具有14种不同显性遗传KATP突变的家族，包括总共33个受影响的个体。16名先证者在出生至3.3岁时出现低血糖，16名中有15名在二氮嗪（一种K-ATP通道激动剂）治疗后血糖控制良好。在29名携带突变的成年人中，14人无症状。与先前报告的显性KATP高胰岛素血症糖尿病风险增加相反，29名成年人中只有4名患有糖尿病。与隐性突变不同，显性遗传的KATP突变亚基在COSm6细胞中表达时通常被转运到质膜。显性突变也导致不同的通道门控缺陷，如显性ABCC8突变减少通道对二磷酸腺苷镁或二氮嗪的反应，而显性KCNJ11突变损害通道开放，即使在没有核苷酸的情况下。这些数据突出了显性KATP高胰岛素血症相对于更常见和更严重的隐性形式的独特特征，包括正常亚基运输的保留，通道活性受损，以及可能在婴儿期逃避检测的轻度低血糖表型，并且通常对二氮嗪药物治疗有反应，而不需要进行胰腺切除术。
Congenital hyperinsulinism is a condition of dysregulated insulin secretion often caused by inactivating mutations of the ATP-sensitive K+ (K-ATP) channel in the pancreatic P cell. Though most disease-causing mutations of the 2 genes encoding K-ATP subunits, ABCC8 (SUR1) and KCNJ11 (Kir6.2), are recessively inherited, some cases of dominantly inherited inactivating mutations have been reported. To better understand the differences between dominantly and recessively inherited inactivating K-ATP, mutations, we have identified and characterized 16 families with 14 different dominantly inherited KATP mutations, including a total of 33 affected individuals. The 16 probands presented with hypoglycemia at ages from birth to 3.3 years, and 15 of 16 were well controlled on diazoxide, a K-ATP channel agonist. Of 29 adults with mutations, 14 were asymptomatic. In contrast to a previous report of increased diabetes risk in dominant KATP hyperinsulinism, only 4 of 29 adults had diabetes. Unlike recessive mutations, dominantly inherited KATP mutant subunits trafficked normally to the plasma membrane when expressed in COSm6 cells. Dominant mutations also resulted in different channel-gating defects, as dominant ABCC8 mutations diminished channel responses to magnesium adenosine diphosphate or diazoxide, while dominant KCNJ11 mutations impaired channel opening, even in the absence of nucleotides. These data highlight distinctive features of dominant KATP hyperinsulinism relative to the more common and more severe recessive form, including retention of normal subunit trafficking, impaired channel activity, and a milder hypoglycemia phenotype that may escape detection in infancy and is often responsive to diazoxide medical therapy, without the need for surgical pancreatectomy.