title: Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome.
abstract: It has been suggested that deficient protein trafficking to the cell membrane is the dominant mechanism associated with type 2 Long QT syndrome (LQT2) caused by Kv11.1 potassium channel missense mutations, and that for many mutations the trafficking defect can be corrected pharmacologically. However, this inference was based on expression of a small number of Kv11.1 mutations. We performed a comprehensive analysis of 167 LQT2-linked missense mutations in four Kv11.1 structural domains and found that deficient protein trafficking is the dominant mechanism for all domains except for the distal carboxy-terminus. Also, most pore mutations--in contrast to intracellular domain mutations--were found to have severe dominant-negative effects when co-expressed with wild-type subunits. Finally, pharmacological correction of the trafficking defect in homomeric mutant channels was possible for mutations within all structural domains. However, pharmacological correction is dramatically improved for pore mutants when co-expressed with wild-type subunits to form heteromeric channels.
authors.affiliation: Department of Biophysics, University of Wisconsin, Madison, Wisconsin 53705, USA.
authors.forename: Corey L
authors.initials: CL
authors.lastname: Anderson
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, Wisconsin 53792, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Kuzmicki
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, Wisconsin 53792, USA.
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Childs
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, Wisconsin 53792, USA.
authors.forename: Caleb J
authors.initials: CJ
authors.lastname: Hintz
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Delisle
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, Wisconsin 53792, USA.
authors.forename: Craig T
authors.initials: CT
authors.lastname: January
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004252:DNA Mutational Analysis; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics*; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D029597:Romano-Ward Syndrome / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers