Carotid Body Dysfunction as a Driver of Sleep-Related Breathing Disorders in Prader-Willi Syndrome

Prader-Willi Syndrome (PWS) is a genetic disorder caused by deficiencies in multiple genes located within the chromosome 15q11–q13 region, which is subject to genomic imprinting. In addition to its hallmark physical, developmental, and behavioral abnormalities, respiratory failure constitutes a major source of morbidity and mortality in individuals with PWS, accounting for approximately 73% of infant deaths, 49% of deaths in children, and 26% in adults; however, the mechanisms linking the genetic alterations in PWS to respiratory instability remain unclear. Breathing disturbances in PWS are characterized by respiratory instability, frequent apneas, and a blunted hypoxic ventilatory response. Because peripheral carotid body (CB) chemoreceptors are essential for hypoxic ventilatory drive, we hypothesized that CB dysfunction may contribute to respiratory disorders in PWS. Accordingly, we aimed to determine whether loss of paternal expression at the PWS imprinting center (IC) impairs CB-mediated chemoreflex control of breathing. PWS IC deletion (PWS-ICdel) mice and wild-type (WT) littermates of both sexes were studied from the neonatal period into adulthood. Growth and survival were monitored, and whole-body plethysmography was used to quantify baseline ventilation, apnea/hypopnea burden, and ventilatory responses to acute hypoxia (FiO 2 ~10% O 2 ). Sleep state and microarousals were also assessed during respiratory stability recordings. Compared to WT littermates, PWS-ICdel neonates showed significant (p< 0.05) reductions in body weight (2.3 ± 0.2 vs. 1.4 ± 0.3 g, WT vs. PWS-ICdel) and lower survival before P15 (41 vs. 100%, WT vs. PWS-ICdel). At baseline, juvenile PWS-ICdel mice (1-2 month age-old) exhibited higher apnea/hypopnea index (4.2 ± 2.0 vs 20.3 ± 4.5 events·h - ¹, WT vs. PWS-ICdel). Also, the duration of apneas/hypopneas were longer in PWS-ICdel compared to WT (1.5 ± 0.3 vs. 4.3 ± 1.1s, WT vs. PWS-ICdel). Notably, we found that PWS-ICdel mice showed a significant reduction in CB-mediated chemoreflex drive as evidenced by low hypoxic ventilatory responses compared to WT (Δ[Formula: see text]E: 134.6 ± 5.5 vs 180.5 ± 10.5%, WT vs. PWS-ICdel). Finally, we found that PWS-ICdel mice displayed altered sleep-wake architecture characterized by a ~25% reduction in sleep latency with a higher incidence of microarousals (8.1 ± 2.5 vs. 12.8 ± 2.9 h - ¹, WT vs. PWS-ICdel). Our findings support the presence of chemoreflex dysfunction in PWS and suggest that reduced chemoreflex drive may play a key role on the development respiratory instability and sleep disruption in PWS. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.