title: Targeted point mutagenesis of mouse Kcnq1: phenotypic analysis of mice with point mutations that cause Romano-Ward syndrome in humans.
abstract: Inherited long QT syndrome is most frequently associated with mutations in KCNQ1, which encodes the primary subunit of a potassium channel. Patients with mutations in KCNQ1 may show only the cardiac defect (Romano-Ward syndrome or RWS) or may also have severe deafness (Jervell and Lange-Nielsen syndrome or JLNS). Targeted disruption of mouse Kcnq1 models JLNS in that mice are deaf and show abnormal ECGs. However, the phenotype is broader than that seen in patients. Most dramatically, the inner ear defects result in a severe hyperactivity/circling behavior, which may influence cardiac function. To understand the etiology of the cardiac phenotype in these mice and to generate a potentially more useful model system, we generated new mouse lines by introducing point mutations associated with RWS. The A340E line phenocopies RWS: the repolarization phenotype is inherited in a dominant manner and is observed independent of any inner ear defect. The T311I line phenocopies JLNS, with deafness associated with inner hair cell malfunction.
authors.affiliation: Laboratory of Mammalian Genes and Development, NICHD/National Institutes of Health, Building 6B Room 2B-206, Bethesda, MD 20892, USA.
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.forename: Bjoern C
authors.initials: BC
authors.lastname: Knollmann
authors.forename: Ebenezer N
authors.initials: EN
authors.lastname: Yamoah
authors.forename: Liping
authors.initials: L
authors.lastname: Nie
authors.forename: Jay C
authors.initials: JC
authors.lastname: Vary
authors.forename: Syevda G
authors.initials: SG
authors.lastname: Sirenko
authors.forename: Anne E
authors.initials: AE
authors.lastname: Greene
authors.forename: Alexander
authors.initials: A
authors.lastname: Grinberg
authors.forename: Sing Ping
authors.initials: SP
authors.lastname: Huang
authors.forename: Steven N
authors.initials: SN
authors.lastname: Ebert
authors.forename: Karl
authors.initials: K
authors.lastname: Pfeifer
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D017931:DNA Primers; D003638:Deafness / Q000235:genetics; D004195:Disease Models, Animal; D004562:Electrocardiography; D016057:Evoked Potentials, Auditory, Brain Stem; D006199:Hair Cells, Auditory, Inner / Q000473:pathology; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D051379:Mice / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D029597:Romano-Ward Syndrome / Q000235:genetics*
chemical_list: D017931:DNA Primers; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496910:Kcnq1 protein, mouse; D024642:Potassium Channels, Voltage-Gated