Newly identified PHOX2B target genes as drug targets in Congenital Central Hypoventilation Syndrome (CCHS)

Congenital Central Hypoventilation Syndrome (CCHS, MIM 209880) is a rare neonatal disease characterized by abnormal ventilatory response to hypoxia and hypercapnia, owing to failure of autonomic respiratory control. Frameshift mutations (5%) and polyalanine triplet expansions (95%) have been detected in the coding region of the transcription factor PHOX2B, responsible for the proper development and function of the ANS. Consistent with its role as transcriptional regulator, transcriptional dysregulation might be an important mechanism of CCHS pathogenesis. Stemming from the fortuitous observation that progestin Desogestrel can relief some symptoms of the disease, by a not yet identified molecular mechanism, and that it enhanced the expression of some relevant PHOX2B target genes in a promoter specific manner, by acting on the activity of the wild type as well as mutant protein, lead us to identify new PHOX2B target genes, by ChIP-seq analysis, as potential pharmacological targets for alternative molecules without contraceptive effects. The expression of PHOX2B target genes will be selectively validated by comparing wild-type and CRISPR-CAS9 Knocked-down PHOX2B expressing IMR32 cells