Trafficking-competent and trafficking-defective KCNJ2 mutations in Andersen syndrome.
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.
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37027-0275, USA.
Leomar Y
LY
Ballester
D Woodrow
DW
Benson
Brenda
B
Wong
Ian H
IH
Law
Katherine D
KD
Mathews
Carlos G
CG
Vanoye
Alfred L
AL
George
D000595:Amino Acid Sequence; D050030:Andersen Syndrome / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics*; D021381:Protein Transport
C489457:KCNJ2 protein, human; D024661:Potassium Channels, Inwardly Rectifying