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Molecular and Cellular Biology, July 2002, p. 4977-4983, Vol. 22, No. 14
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.14.4977-4983.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Predisposition to Arrhythmia and Autonomic Dysfunction in Nhlh1-Deficient Mice

Tiziana Cogliati,1 Deborah J. Good,1,{dagger} Mark Haigney,2 Petra Delgado-Romero,1 Michael A. Eckhaus,3 Walter J. Koch,4 and Ilan R. Kirsch1*

Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20889,1 Division of Cardiology, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814,2 Veterinary Resources Program, Office of Research Services, Office of the Director, National Institutes of Health, Bethesda, Maryland 20892,3 Department of Surgery, Duke University Medical Center, Durham, North Carolina 277104

Received 12 March 2002/ Accepted 17 April 2002

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.

* Corresponding author. Mailing address: NCI-CCR Genetics Branch, National Naval Medical Center, 8901 Wisconsin Ave., Bldg. 8, Rm. 5101, Bethesda, MD 20889-5105. Phone: (301) 496-0909. Fax: (301) 496-0047. E-mail: kirschi{at}exchange.nih.gov.

{dagger} Present address: Department of Veterinary and Animal Sciences, Center for Neuroendocrine Studies, University of Massachusetts, Amherst, MA 01003.

Molecular and Cellular Biology, July 2002, p. 4977-4983, Vol. 22, No. 14
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.14.4977-4983.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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