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Sleep-disordered breathing in newborn mice heterozygous for the transcription factor Phox2b
Estelle Durand1, Stéphane Dauger, Alexandre Pattyn
1INSERM U676, Hôpital Robert-Debré, 48 Boulevard Sérurier, 75019 Paris, France.
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.
Insights
Newborn mice with a Phox2b gene deletion exhibited significant sleep-disordered breathing, mirroring a key feature of Central Congenital Hypoventilation Syndrome (CCHS). This research provides a valuable model for studying CCHS in infants.
Area of Science:
- Genetics
- Neuroscience
- Respiratory Physiology
Background:
- Central Congenital Hypoventilation Syndrome (CCHS) is a rare, inherited disorder affecting breathing regulation during sleep.
- Mutations in the Phox2b homeobox gene are frequently identified in CCHS patients.
Purpose of the Study:
- To investigate if heterozygous targeted deletion of the Phox2b gene in newborn mice results in sleep-disordered breathing.
- To establish a potential animal model for studying CCHS.
Main Methods:
- Breathing patterns were assessed in 5-day-old wild-type and Phox2b mutant mice using whole-body plethysmography.
- Sleep-wake states were classified through nuchal electromyography (EMG) and behavioral observation.
Main Results:
- Mutant mice displayed approximately six times more total sleep apnea time compared to wild-type controls.
- Ventilation during active sleep was significantly reduced by 21% in mutant pups.
- No significant differences in apnea time or ventilation were observed during wakefulness between groups.
Conclusions:
- Phox2b(+/-) mutant mice exhibit sleep-disordered breathing, partially modeling the primary characteristic of CCHS.
- These findings suggest Phox2b plays a crucial role in respiratory control during sleep.
- The mutant mouse model offers a platform for further investigation into CCHS pathogenesis and potential therapies.
