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Sleep-disordered Breathing in Newborn Mice Heterozygous for the Transcription Factor Phox2b

INSERM U676, and Service de Réanimation, Hôpital Robert-Debré; and CNRS UMR 8542, Ecole Normale Supérieure, Paris, France

Correspondence and requests for reprints should be addressed to Jorge Gallego, Ph.D., INSERM U676, Hôpital Robert-Debré, 48 Boulevard Sérurier, 75019 Paris, France. E-mail: gallego{at}rdebre.inserm.fr

Rationale: Central congenital hypoventilation syndrome (CCHS) is a rare autosomal dominant syndrome present from birth, and characterized by depressed ventilation during sleep. Heterozygous mutations of the homeobox gene Phox2b were recently found in a very high proportion of patients. Objectives: To determine whether newborn mice with heterozygous targeted deletion of the transcription factor Phox2b would display sleep-disordered breathing. Methods: We measured breathing pattern using whole-body plethysmography in wild-type and mutant 5-day-old mice, and we classified sleep–wake states using nuchal EMG and behavioral scores. Results: We found that sleep apnea total time was approximately six times longer (8.9 ± 12 vs. 1.5 ± 2.2 seconds, p < 0.0015), and ventilation during active sleep was 21% lower (18.4 ± 5.1 vs. 23.3 ± 5.5 ml/g/second, p < 0.006) in mutant than in wild-type pups. During wakefulness, apnea time and ventilation were not significantly different between mutant and wild-type pups. Mutant and wild-type pups showed highly similar sleep–wake states. Conclusion: Although their respiratory phenotype was much less severe than CCHS, the Phox2b^+/– mutant mice showed sleep-disordered breathing, which partially modeled the key feature of CCHS.

Key Words: apnea • hypoventilation • Ondine syndrome

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