Fig. 1.

Genotype and respiratory physiological phenotypes of the proband and transgenic mouse model. a PHOX2B contains three exons and proband 8-nucleotide frameshift mutation in exon 3 is shown. Nucleotide number refers to nucleotide position of GenBank accession number CCDS 3463.1. Wild-type PHOX2B protein is 314 amino acids long; PHOX2B∆8 mutation results in loss of the 20-alanine repeat domain and generates a protein of 355 amino acids. b Polysomnographic recording from the proband while on Synchronized Intermittent Mandatory Ventilation (SIMV) and after switching to continuous positive airway pressure (CPAP). Note the rapid decrease in oxygen saturation (blue arrow) and increase in carbon dioxide (pink arrow) levels. Values of E_TCO₂ at each epoch shown. When challenged with persistent hypercarbia and hypoxemia during CPAP, the proband showed no increase in respiratory effort. Heart rate variability during the challenge was minimal. EKG electrocardiogram, SpO ₂ oxygen saturation, E _T CO ₂ end-tidal CO₂, Nasal nasal airflow, Chest chest wall movements from respiratory inductance plethysmography. CPAP pressure of 5 cm H₂O was used. SIMV rate was 45 breaths/min. “Early” refers to 45 s after switching to CPAP, “late” refers to 75 s after switching to CPAP. Time scale is shown. c Targeting construct of patient-specific mouse model. Human PHOX2B exon 3 containing patient-specific PHOX2B mutation (denoted in blue color) is inserted following unmodified, non-mutated mouse Phox2b exon 3 flanked by loxP sites, to allow conditional expression of mutant gene by cre recombinase. For detailed generation of transgenic mouse line see Figure S4. d Endogenous respiratory output. Integrated C4 inspiratory activity from E18.5 control and Hprt-cre, Phox2b∆8 mutant mice under baseline (left) and stimulated (1 μM substance P, right) conditions. Note lack of response in Phox2b∆8 mouse brainstem (n = 4, a representative recording shown)