Mutations at the same residue (R50) of Kir6.2 (KCNJ11) that cause neonatal diabetes produce different functional effects
Mutations at the same residue (R50) of Kir6.2 (KCNJ11) that cause neonatal diabetes produce different functional effects
复制标题
DOI：
10.2337/db05-1640
复制
发表时间：
2006-06-01
期刊：
影响因子：
7.7
通讯作者：
Ashcroft, Frances M.
中科院分区：
文献类型：
--
作者：
Shimomura, Kenju;Girard, Christophe A. J.;Ashcroft, Frances M.
人Kir6.2基因（KCNJ 11）的杂合突变是ATP敏感性K+通道（K-ATP通道）的孔形成亚基，是新生儿糖尿病的常见原因。我们发现了一种新的KCNJ 11突变R50 Q，它会导致永久性新生儿糖尿病（PNDM），而不会引起神经系统问题。我们研究了这个突变和另一个在同一个残基（R50 P），导致PNDM与发育迟缓的功能影响。通过在非洲爪蟾卵母细胞中异源表达来检查野生型或突变型Kir6.2/SUR 1通道。这两种突变增加静息全细胞电流通过同型和杂合KATP通道减少通道抑制ATP，在Mg 2+的存在下，效果更大。然而，ATP敏感性降低的幅度（以及全细胞电流的增加）对于R50 P突变来说要大得多。这与更严重的表型一致。单R50 P通道动力学（在ATP的情况下）没有不同于野生型，表明突变主要影响ATP结合和/或转导。这支持了R50位于Kir6.2的ATP结合位点的观点。磺酰脲类药物甲苯磺丁脲阻断杂合型R50 Q（89%）和R50 P（84%）通道的作用仅略低于野生型通道（98%），这表明磺酰脲类药物治疗可能对具有任一突变的患者有益。
Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive K+ channel (K-ATP channel), are a common cause of neonatal diabetes. We identified a novel KCNJ11 mutation, R50Q, that causes permanent neonatal diabetes (PNDM) without neurological problems. We investigated the functional effects this mutation and another at the same residue (R50P) that led to PNDM in association with developmental delay. Wild-type or mutant Kir6.2/SUR1 channels were examined by heterologous expression in Xenopus oocytes. Both mutations increased resting whole-cell currents through homomeric and heterozygous KATP channels by reducing channel inhibition by ATP, an effect that was larger in the presence of Mg2+. However the magnitude of the reduction in ATP sensitivity (and the increase in the whole-cell current) was substantially larger for the R50P mutation. This is consistent with the more severe phenotype. Single-R50P channel kinetics (in the absence of ATP) did not differ from wild type, indicating that the mutation primarily affects ATP binding and/or transduction. This supports the idea that R50 lies in the ATP-binding site of Kir6.2. The sulfonylurea tolbutamide blocked heterozygous R50Q (89%) and R50P (84%) channels only slightly less than wild-type channels (98%), suggesting that sulfonylurea therapy may be of benefit for patients with either mutation.