Targeted Disruption of the Kcnq1 Gene Produces a Mouse Model of Jervell and Lange-Nielsen Syndrome

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 5; pp. 2526 - 2531
• Main Authors: Casimiro, Mathew C., Knollmann, Björn C., Ebert, Steven N., Vary, Jay C., Greene, Anne E., Franz, Michael R., Grinberg, Alexander, Huang, Sing Ping, Pfeifer, Karl
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27.02.2001; National Acad Sciences; The National Academy of Sciences
• Subjects: Action Potentials; Animals; Base Sequence; Biological Sciences; Deafness; Disease Models, Animal; DNA Primers; Ear, Inner - metabolism; Ear, Inner - pathology; Electrocardiography; Endolymph; Exons; Genes; Genetics; Hair cells; Homeostasis - genetics; Inner ear; Jervell and Lange-Nielsen syndrome; kcng1 gene; KCNQ Potassium Channels; KCNQ1 Potassium Channel; Long QT Syndrome - genetics; Long QT Syndrome - physiopathology; Mice; Mice, Mutant Strains; Mutation; Phenotype; Phenotypes; Potassium Channels - genetics; Potassium Channels - physiology; Potassium Channels, Voltage-Gated; Proteins; Rodents
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.041398998

KCNQ1 encodes KCNQ1, which belongs to a family of voltage-dependent K+ ion channel proteins. KCNQ1 associates with a regulatory subunit, KCNE1, to produce the cardiac repolarizing current, IKs. Loss-of-function mutations in the human KCNQ1 gene have been linked to Jervell and Lange-Nielsen Syndrome (JLNS), a disorder characterized by profound bilateral deafness and a cardiac phenotype. To generate a mouse model for JLNS, we created a line of transgenic mice that have a targeted disruption in the Kcnq1 gene. Behavioral analysis revealed that the Kcnq1-/- mice are deaf and exhibit a shaker/waltzer phenotype. Histological analysis of the inner ear structures of Kcnq1-/- mice revealed gross morphological anomalies because of the drastic reduction in the volume of endolymph. ECGs recorded from Kcnq1-/- mice demonstrated abnormal T- and P-wave morphologies and prolongation of the QT and JT intervals when measured in vivo, but not in isolated hearts. These changes are indicative of cardiac repolarization defects that appear to be induced by extracardiac signals. Together, these data suggest that Kcnq1-/- mice are a potentially valuable animal model of JLNS.