title: Identification of Kv11.1 isoform switch as a novel pathogenic mechanism of long-QT syndrome.
abstract: BACKGROUND
  The KCNH2 gene encodes the Kv11.1 potassium channel that conducts the rapidly activating delayed rectifier current in the heart. The relative expression of the full-length Kv11.1a isoform and the C-terminally truncated Kv11.1a-USO isoform plays an important role in regulation of channel function. The formation of C-terminal isoforms is determined by competition between the splicing and alternative polyadenylation of KCNH2 intron 9. It is not known whether changes in the relative expression of Kv11.1a and Kv11.1a-USO can cause long-QT syndrome.
  
  
  RESULTS
  We identified a novel KCNH2 splice site mutation in a large family. The mutation, IVS9-2delA, is a deletion of the A in the AG dinucleotide of the 3' acceptor site of intron 9. We designed an intron-containing full-length KCNH2 gene construct to study the effects of the mutation on the relative expression of Kv11.1a and Kv11.1a-USO at the mRNA, protein, and functional levels. We found that this mutation disrupted normal splicing and resulted in exclusive polyadenylation of intron 9, leading to a switch from the functional Kv11.1a to the nonfunctional Kv11.1a-USO isoform in HEK293 cells and HL-1 cardiomyocytes. We also showed that IVS9-2delA caused isoform switch in the mutant allele of mRNA isolated from patient lymphocytes.
  
  
  CONCLUSIONS
  Our findings indicate that the IVS9-2delA mutation causes a switch in the expression of the functional Kv11.1a isoform to the nonfunctional Kv11.1a-USO isoform. Kv11.1 isoform switch represents a novel mechanism in the pathogenesis of long-QT syndrome.
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR (Q.G., M.R.S., V.D., Z.Z.); and Lankenau Institute for Medical Research and Lankenau Medical Center, Jefferson Medical College, Philadelphia, PA (L.Z.).
authors.forename: Qiuming
authors.initials: Q
authors.lastname: Gong
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR (Q.G., M.R.S., V.D., Z.Z.); and Lankenau Institute for Medical Research and Lankenau Medical Center, Jefferson Medical College, Philadelphia, PA (L.Z.).
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Stump
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR (Q.G., M.R.S., V.D., Z.Z.); and Lankenau Institute for Medical Research and Lankenau Medical Center, Jefferson Medical College, Philadelphia, PA (L.Z.).
authors.forename: Vivianne
authors.initials: V
authors.lastname: Deng
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR (Q.G., M.R.S., V.D., Z.Z.); and Lankenau Institute for Medical Research and Lankenau Medical Center, Jefferson Medical College, Philadelphia, PA (L.Z.).
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR (Q.G., M.R.S., V.D., Z.Z.); and Lankenau Institute for Medical Research and Lankenau Medical Center, Jefferson Medical College, Philadelphia, PA (L.Z.). zhouzh@ohsu.edu.
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D002460:Cell Line; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D007438:Introns; D008133:Long QT Syndrome / Q000235:genetics / Q000473:pathology*; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D026723:Polyadenylation; D022821:RNA Splice Sites; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D022821:RNA Splice Sites; D012333:RNA, Messenger
keywords: long QT syndrome; potassium channels