Abstract
Abstract
Congenital central hypoventilation syndrome (CCHS) is a rare autonomic nervous system disorder characterized by defective autonomic control of breathing resulting in life-threatening hypoventilation, particularly during sleep. CCHS is most commonly caused by pathogenic mutations in the transcription factor PHOX2B, broadly classified into polyalanine repeat expansion mutations (PARMs) and non-polyalanine repeat mutations (NPARMs). These differ in prevalence, clinical severity, and associated comorbidities. Here, we integrate and review evidence from studies in vivo models, immortalized in vitro cell lines, and patient-derived cellular models to elucidate how PHOX2B mutations drive CCHS pathology. Mouse models have revealed lineage-specific vulnerabilities across central, peripheral, and enteric autonomic circuits, with pronounced defects in the retrotrapezoid nucleus. Immortalized cell models have enabled mechanistic dissection of mutation-specific effects on PHOX2B localization, dimerization, transcriptional regulation, and protein homeostasis. At the same time, patient-derived cellular systems recapitulate key aspects of human disease, including altered differentiation trajectories and respiratory-relevant neuronal dysfunction. Collectively, these complementary experimental systems demonstrate that PHOX2B mutations disrupt both developmental and post-developmental mechanisms underlying autonomic dysfunction. Importantly, no single model fully recapitulates human CCHS, highlighting the need for integrated model systems to accelerate mechanistic discovery and therapeutic development.