PATHOGENETIC MECHANISMS UNDERLYING TWO INHERITED DISORDERS OF NEURAL CREST DEVELOPMENT: HIRSCHSPRUNGS DISEASE AND CONGENITAL CENTRAL HYPOVENTILATION SYNDROME

Hirschsprung (HSCR) disease is regarded as one of the “simplest” among the complex, multigenic inherited disorders, being only three the estimated number of genes whose changes can contribute to disease development. The RET proto-oncogene is one of these three genes, already demonstrated to play a crucial role in conferring different degrees of susceptibility to HSCR development. Indeed, in the human population a series of RET common variants recur, displaying a mild effect on the protein function, which under still unknown conditions can influence and modify the individual risk of HSCR development. The HSCR phenotype can be found in association with 15-20% of patients affected with Congenital Central Hypoventilation Syndrome (CCHS), another neurocristopathy we intend to study. CCHS is a very rare neonatal disorder characterized by failure of autonomic respiratory control so that affected children require ventilatory support during sleep. Defects of the PHOX2B gene are resulted responsible of simple mendelian inheritance of CCHS.With the present project proposal, starting from what already known about the genetics underlying HSCR and CCHS development, we intend to investigate the pathogenetic mechanisms, and related molecular details, associating 1) RET common variants (namely variant versions of the RET gene present, though with different frequencies, in both patients and healthy individuals) with predisposition to or protection against HSCR development, and 2) different types of PHOX2B mutations with the developemnt of various degrees of CCHS severity (genotype-phenotype correlation).