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

Introduction: 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 autonomic nervous system. Consistent with its role as transcriptional regulator, it is reasonable to suppose that transcriptional dysregulation might be an important mechanism of CCHS pathogenesis. Current research on treatments of CCHS is focused on counteracting the toxic effects of the mutated PHOX2B protein, and stemming from the fortuitous observation that progestin Desogestrel can relief some symptoms of the disease, by a not yet identified molecular mechanism,lead us to identify new PHOX2B target genes as potential pharmacological targets for alternative molecules without contraceptive effects. Methods: Identification of PHOX2B regulated genes has been carried-out by ChIP-seq analysis in IMR32 cells. The expression of PHOX2B target genes will be selectively validated by comparing wild-type and CRISPR-CAS9 Knocked-down PHOX2B expressing IMR32 cells. Results and conclusion: Gene Ontology analysis of the set of peak-associated genes identified several enriched terms in categories consistent with PHOX2B role during autonomic nervous system development and maintenance. Further, we show that Desogestrel 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.