Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.
Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.
复制标题
婴儿期高胰岛素血症：新的 ABCC8 和 KCNJ11 突变以及其他基因座异质性的证据。
DOI：
--
复制
发表时间：
2004
影响因子：
5.8
通讯作者：
B. Glaser
中科院分区：
文献类型：
--
作者：
Sharona Tornovsky;A. Crane;K. Cosgrove;K. Hussain;Judith Lavie;M. Heyman;Y. Nesher;N. Kuchinski;E. Ben;O. Shatz;Efrat Nahari;T. Potikha;D. Zangen;Y. Tenenbaum‐Rakover;L. de Vries;J. Argente;R. Gracía;H. Landau;A. Eliakim;K. Lindley;M. Dunne;L. Aguilar;B. Glaser
婴儿期高胰岛素血症是一种遗传异质性疾病，其特征是胰岛素分泌失调，导致严重的低血糖。到目前为止，已经涉及五种不同基因的突变，磺酰脲受体（SUR 1，ABCC 8），内向整流钾通道（K（IR）6.2，KCNJ 11），葡萄糖激酶（GCK），谷氨酸脱氢酶（GLUD 1）和短链3-羟酰辅酶A脱氢酶（SCHAD）。先前的报告表明，在40%的患者中，在这些基因中的任何一个中都没有发现突变，这表明了额外的基因座异质性。然而，以前的研究没有使用直接测序来筛选所有五个基因，直接测序是突变检测中最敏感的技术。我们选择了15例婴儿期高胰岛素血症患者，并对ABCC 8和KCNJ 11的启动子和所有编码外显子以及内含子/外显子边界进行了系统测序。如果未发现突变，则对GCK、GLUD 1和SCHAD的编码序列和内含子/外显子边界进行测序。在ABCC 8编码区发现7个新突变，在KCNJ 11编码区发现1个突变，在筛选的两个启动子区中各发现1个新突变。对6名患者的β细胞进行的功能研究显示，其中5名患者的ATP敏感性K+通道功能异常;第6名患者的通道活性正常，未发现突变。在异源表达系统中，每个启动子突变使报告基因的表达降低约60%。在4例患者（27%）中，未发现突变。因此，进一步的遗传异质性，建议在这种疾病。这些患者代表了可用于搜索其他候选基因中的突变的队列。
Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (K(IR)6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on beta-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.
登录
查看更多内容
影响因子：
20.3
作者：
L. Aguilar-Bryan;J. Bryan
通讯作者：
L. Aguilar-Bryan;J. Bryan
谷氨酸脱氢酶抑制性三磷酸鸟苷结合域发生调节突变的儿童高胰岛素血症/高氨血症综合征。
DOI：
10.1210/jcem.86.4.7414
发表时间：
2001
期刊：
The Journal of clinical endocrinology and metabolism.
影响因子：
--
作者：
MacMullen,C;Fang,J;Hsu,BY;Kelly,A;deLonlay-Debeney,P;Saudubray,JM;Ganguly,A;Smith,TJ;Stanley,CA;Hyperinsulinism/hyperammonemiaContributingInvestigators
通讯作者：
Hyperinsulinism/hyperammonemiaContributingInvestigators
影响因子：
158.5
作者：
Glaser, B;Kesavan, P;Herold, KC
通讯作者：
Herold, KC
影响因子：
158.5
作者：
Stanley, CA;Lieu, YK;Poncz, M
通讯作者：
Poncz, M
影响因子：
56.9
作者：
THOMAS, PM;COTE, GJ;BRYAN, J
通讯作者：
BRYAN, J