Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy
Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy
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DOI：
10.1093/hmg/5.11.1809
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发表时间：
1996-11-01
影响因子：
3.5
通讯作者：
Lightner, E
中科院分区：
文献类型：
--
作者：
Thomas, P;Ye, YY;Lightner, E
胰岛β细胞ATP敏感性钾通道的关闭启动了一系列导致胰岛素分泌的事件，β细胞ATP敏感性钾电流可以通过共表达内向整流Kir6.2和磺酰脲受体（SUR）来重建，磺酰脲受体是ATP结合盒超家族的成员。已在患有家族性婴儿持续性高胰岛素血症低血糖（PHHI）的个体中发现了SUR突变，PHHI是一种常染色体隐性葡萄糖代谢疾病，与染色体11 p15.1有关，其特征是胰岛素分泌不受调节和严重低血糖，由于Kir6.2位点位于染色体11p15.1上的SUR基因的5个碱基（kb）内，并且它是β细胞K-ATP通道的必要成员，因此我们认为Kir6.2是PHHI的候选基因。我们在一个近亲家庭的一个严重患有PHHI的儿童的基因组DNA中鉴定了Kir6.2的纯合点突变，该突变被预测通过用脯氨酸取代亮氨酸残基（L147 P）来破坏内向整流器的保守的α螺旋第二跨膜（M2）结构域，似乎导致PHHI表型，表明Kir6.2对于胰岛素释放的正常调节是必需的，尽管不是充分的。
Closure of ATP-sensitive potassium channels in pancreatic islet beta-cells initiates a cascade of events that leads to insulin secretion, beta-Cell ATP-sensitive potassium currents can be reconstituted by coexpression of the inward rectifier Kir6.2 and the sulfonylurea receptor (SUR), a member of the ATP-binding cassette superfamily. Mutations in SUR have been identified in individuals affected with familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder of glucose metabolism which is linked to chromosome 11p15.1 and characterized by unregulated secretion of insulin and profound hypoglycemia, Because the Kir6.2 locus is within 5 kilobases (kb) of the SUR gene on chromosome 11p15.1 and it is a necessary member of the beta-cell K-ATP channel, we considered Kir6.2 as a candidate gene for PHHI. We identified a homozygous point mutation in Kir6.2 in the genomic DNA of a child, severely affected with PHHI, from a consanguineous family, This mutation is predicted to disrupt the conserved alpha-helical second transmembrane (M2) domain of the inward rectifier by substitution of a proline for a leucine residue (L147P), Mutation of Kir6.2 like SUR, appears to lead to the PHHI phenotype suggesting that Kir6.2 is necessary, although not sufficient, for normal regulation of insulin release.