title: Mutations underlying Episodic Ataxia type-1 antagonize Kv1.1 RNA editing.
abstract: Adenosine-to-inosine RNA editing in transcripts encoding the voltage-gated potassium channel Kv1.1 converts an isoleucine to valine codon for amino acid 400, speeding channel recovery from inactivation. Numerous Kv1.1 mutations have been associated with the human disorder Episodic Ataxia Type-1 (EA1), characterized by stress-induced ataxia, myokymia, and increased prevalence of seizures. Three EA1 mutations, V404I, I407M, and V408A, are located within the RNA duplex structure required for RNA editing. Each mutation decreased RNA editing both in vitro and using an in vivo mouse model bearing the V408A allele. Editing of transcripts encoding mutant channels affects numerous biophysical properties including channel opening, closing, and inactivation. Thus EA1 symptoms could be influenced not only by the direct effects of the mutations on channel properties, but also by their influence on RNA editing. These studies provide the first evidence that mutations associated with human genetic disorders can affect cis-regulatory elements to alter RNA editing.
authors.affiliation: Department of Molecular Physiology &Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, United States.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ferrick-Kiddie
authors.affiliation: Eugene Bell Center for Regenerative Biology and Tissue Engineering, The Marine Biological Laboratory, Woods Hole, MA 02543, United States.|Institute of Neurobiology, University of Puerto Rico Medical Sciences Campus, San Juan, PR 00901, United States.
authors.forename: Joshua J C
authors.initials: JJ
authors.lastname: Rosenthal
authors.affiliation: Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Ayers
authors.affiliation: Department of Molecular Physiology &Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, United States.|Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Emeson
mesh_terms: D000200:Action Potentials; D000483:Alleles; D000818:Animals; D001259:Ataxia / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051662:Kv1.1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D023421:Models, Animal; D016297:Mutagenesis, Site-Directed; D020385:Myokymia / Q000378:metabolism / Q000473:pathology; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D017393:RNA Editing; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism; D014981:Xenopus / Q000254:growth & development
chemical_list: D051662:Kv1.1 Potassium Channel