Trafficking-competent and trafficking-defective KCNJ2 mutations in Andersen syndrome.
Trafficking-competent and trafficking-defective KCNJ2 mutations in Andersen syndrome.
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DOI：
10.1002/humu.9418
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发表时间：
2006-04-01
期刊：
影响因子：
3.9
通讯作者：
George, Alfred L Jr
中科院分区：
文献类型：
--
作者：
Ballester, Leomar Y;Benson, D Woodrow;George, Alfred L Jr
编码人类内向整流钾通道Kir2.1的基因KCNJ2突变已在Andersen综合征（或Andersen- tawil综合征）中被发现，Andersen- tawil综合征是一种以周期性麻痹、心律失常和畸形为特征的遗传性疾病。我们鉴定并鉴定了两个新的KCNJ2突变（c.220A>G/p）。T74A和C . 443g >C/p。G144A)与Andersen综合征相关。在HEK-293细胞中异源表达重组野生型人KCNJ2 cDNA （WT-KCNJ2）会产生强大的内向整流电流，但我们没有观察到表达任何突变体的细胞产生可测量的电流。共转染WT-KCNJ2和任一突变体的细胞表现出明显较低的全细胞电流振幅，这与突变体通道对WT-KCNJ2的显性负抑制一致。p.T74A和p.G144A均表现出强劲的质膜表达，但先前报道的第三个等位基因（p.C101R）表现出受损的转运。我们的研究结果证明了两种与Andersen综合征相关的新型贩运能力KCNJ2突变的功能后果，并扩展了我们对该疾病等位基因多样性的认识。
Mutations in KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1, have been identified in Andersen syndrome (or Andersen-Tawil syndrome), an inherited disorder characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. We identified and characterized two novel KCNJ2 mutations (c.220A>G/p.T74A and c.443G>C/p.G144A) associated with Andersen syndrome. Heterologous expression of a recombinant wild type human KCNJ2 cDNA (WT-KCNJ2) in HEK-293 cells results in robust inward rectifying currents, but we did not observe measurable currents from cells expressing either mutant. Cells co-transfected with WT-KCNJ2 and either mutant exhibited substantially lower whole-cell current amplitude consistent with a dominant-negative suppression of WT-KCNJ2 by the mutant channels. Both p.T74A and p.G144A exhibit robust plasma membrane expression, but a third previously reported allele (p.C101R) exhibited impaired trafficking. Our results demonstrate functional consequences of two novel trafficking-competent KCNJ2 mutations associated with Andersen syndrome and expand our knowledge of allelic diversity in this disease.