Dominantly acting ABCC8 mutations in patients with medically unresponsive hyperinsulinaemic hypoglycaemia.
Dominantly acting ABCC8 mutations in patients with medically unresponsive hyperinsulinaemic hypoglycaemia.
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DOI：
10.1111/j.1399-0004.2010.01476.x
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发表时间：
2011-06
影响因子：
3.5
通讯作者：
Ellard S
中科院分区：
文献类型：
--
作者：
Flanagan SE;Kapoor RR;Banerjee I;Hall C;Smith VV;Hussain K;Ellard S
Flanagan SE，Kapoor RR，Banerjee I，Hall C，Smith VV，Hussain K，Ellard S.药物无反应性高胰岛素血症低血糖患者的显性ABCC8突变编码三磷酸腺苷敏感性钾（KATP）通道亚单位磺脲受体1（SUR1）和内向整流钾通道亚单位（Kir6.2）的ABCC8和KCNJ11基因的隐性失活突变是高胰岛素血症性低血糖（HH）的最常见原因。这些患者中的大多数对KATP通道激动剂二氮嗪治疗无反应。显性失活ABCC8和KCNJ11突变不太常见，但通常与对二氮嗪治疗有反应的轻度低血糖相关。我们研究了来自四个家族的五名HH患者，他们对二氮嗪无反应，需要进行近全胰腺切除术。通过测序和剂量分析寻找KCNJ11和ABCC8中的突变。在4名先证者中发现了3个新的杂合ABCC8错义突变（G1485E、D1506E和M1514K）。所有突变影响位于SUR1亚基的核苷酸结合结构域2内的残基。对家族成员的检测表明，突变是在一个家系中以显性遗传从头发生的。本研究扩展了与显性KATP通道突变相关的临床表型，以包括需要近全胰腺切除术的重度先天性HH以及较轻度的二氮嗪反应性低血糖。显性与隐性突变的鉴别不能预测临床病程，但对估计未来兄弟姐妹和后代中HH的风险很重要。
Flanagan SE, Kapoor RR, Banerjee I, Hall C, Smith VV, Hussain K, Ellard S. Dominantly acting ABCC8 mutations in patients with medically unresponsive hyperinsulinaemic hypoglycaemia. Recessive inactivating mutations in the ABCC8 and KCNJ11 genes encoding the adenosine triphosphate-sensitive potassium (KATP) channel subunit sulphonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel subunit (Kir6.2) are the most common cause of hyperinsulinaemic hypoglycaemia (HH). Most of these patients do not respond to treatment with the KATP channel agonist diazoxide. Dominant inactivating ABCC8 and KCNJ11 mutations are less frequent, but are usually associated with a milder form of hypoglycaemia that is responsive to diazoxide therapy. We studied five patients from four families with HH who were unresponsive to diazoxide and required a near total pancreatectomy. Mutations in KCNJ11 and ABCC8 were sought by sequencing and dosage analysis. Three novel heterozygous ABCC8 mis-sense mutations (G1485E, D1506E and M1514K) were identified in four probands. All the mutations affect residues located within the Nucleotide Binding Domain 2 of the SUR1 subunit. Testing of family members showed that the mutations had arisen de novo with dominant inheritance in one pedigree. This study extends the clinical phenotype associated with dominant KATP channel mutations to include severe congenital HH requiring near total pancreatectomy in addition to a milder form of diazoxide responsive hypoglycaemia. The identification of dominant vs recessive mutations does not predict clinical course but it is important for estimating the risk of HH in future siblings and offspring.
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影响因子：
5.8
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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