Predisposition to arrhythmia and autonomic dysfunction in Nhlh1-deficient mice.
Nhlh1 is a basic helix-loop-helix transcription factor whose expression is restricted to the nervous system and which may play a role in neuronal differentiation. To directly study Nhlh1 function, we generated null mice. Homozygous mutant mice were predisposed to premature, adult-onset, unexpected death. Electrocardiograms revealed decreased total heart rate variability, stress-induced arrhythmia, and impaired baroreceptor sensitivity. This predisposition to arrhythmia is a likely cause of the observed death in the mutant mice. Heterozygosity for the closely related transcription factor Nhlh2 increased the severity of the Nhlh1-null phenotype. No signs of primary cardiac structural or conduction abnormalities could be detected upon necropsy of the null mice. The pattern of altered heart rhythm observed in basal and experimental conditions (stress and pharmacologically induced) suggests that a deficient parasympathetic tone may contribute to the arrhythmia in the Nhlh1-null mouse. The expression of Nhlh1 in the developing brain stem and in the vagal nuclei in the wild-type mouse further supports this hypothesis. The Nhlh1 mutant mouse may thus provide a model to investigate the contribution of the autonomic nervous system to arrhythmogenesis.
Cogliati
Tiziana
T
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20889, USA.
Good
Deborah J
DJ
Haigney
Mark
M
Delgado-Romero
Petra
P
Eckhaus
Michael A
MA
Koch
Walter J
WJ
Kirsch
Ilan R
IR
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D001342:Autonomic Nervous System Diseases / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D051792:Basic Helix-Loop-Helix Proteins; D001919:Bradycardia / Q000503:physiopathology; D001933:Brain Stem / Q000196:embryology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D004242:Diving / Q000502:physiology; D004562:Electrocardiography; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D006329:Heart Conduction System / Q000503:physiopathology; D006339:Heart Rate / Q000502:physiology; D006579:Heterozygote; D006720:Homozygote; D017403:In Situ Hybridization; D008136:Longevity / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011311:Pressoreceptors / Q000503:physiopathology
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; C498272:Nhlh1 protein, mouse