Trafficking-competent and trafficking-defective KCNJ2 mutations in Andersen syndrome

✍ Scribed by Leomar Y. Ballester; D. Woodrow Benson; Brenda Wong; Ian H. Law; Katherine D. Mathews; Carlos G. Vanoye; Alfred L. George Jr.

• Book ID: 102860012
• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 564 KB
• Volume: 27
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.9418

✦ Synopsis

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.