PHOX2B polyalanine repeat mutation alters the transcriptome of neuronal progenitor cells in congenital central...

Mutation in paired-like homeobox 2B (PHOX2B) is used as the diagnostic marker of Congenital Central Hypoventilation Syndrome (CCHS). The mutant gene/protein affects neural crest cells embryonic development which leads to congenital central hypoventilation syndrome (CCHS). When individuals also have Hirschsprung's disease (HSCR) with CCHS it is known as Haddad syndrome (HS). Previous studies on CCHS/HS have mainly focused on the conformational dynamics of the mutant protein and have remained controversial. Here we performed RNA-sequencing on the patient derived neuroepithelial stem cells (NESCs), pertinent to the neurodevelopmental phenotype in CCHS/HS, and found that the PHOX2B-PARM has a profound impact on the transcriptional profile of the cells. The single copy of PHOX2B-PARM in heterozygote cells led to >8 fold differentially expressed genes. This include genes e.g., STMN2, L1CAM, ONECUT2 and NFASC, that are reported to have role in neurodevelopment. In the patient cells there was a significant enrichment of genes related to neuronal development and synapse organization mainly driven by L1CAM interactions and synaptogenesis signaling pathway. Our results not only highlight the use of a suitable model of CCHS/HS but also provide a clear path for future experimental validation.