Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome.
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, I(Ks). 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.
Laboratory for Mammalian Genes and Development, National Institute of Child Health and Human Development/National Institutes of Health, Bethesda, MD 20892, USA.
M C
MC
Casimiro
B C
BC
Knollmann
S N
SN
Ebert
J C
JC
Vary
A E
AE
Greene
M R
MR
Franz
A
A
Grinberg
S P
SP
Huang
K
K
Pfeifer
D000200:Action Potentials; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D007758:Ear, Inner / Q000378:metabolism / Q000473:pathology; D004562:Electrocardiography; D006706:Homeostasis / Q000235:genetics; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated
D017931:DNA Primers; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496910:Kcnq1 protein, mouse; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated