Ricerc@Sapienza

Human pyridoxal 5'-phosphate oxidase (PNPO) is a key enzyme in vitamin B6 metabolism and is responsible for maintaining pyridoxal 5'-phosphate (PLP) homeostasis in tissues. PLP, the active form of vitamin B6, is a cofactor for over 160 known PLP-dependent enzymes serving vital roles in pathways involving sugars, lipids, amino acids, heme, and nucleotides. PLP-dependent enzymes participate in the metabolism of several neurotransmitters such as dopamine, serotonin, epinephrine, and gamma-aminobutyric acid. The activity of PLP-enzymes is essential for the correct functioning of the central nervous system, and relies on an appropriate availability of PLP in neuronal cells. Deficiency of PNPO, the enzyme that catalyzes the last step of PLP biosynthesis, results in a severe neonatal encephalopathy. Recent studies have widened the clinical phenotype of this condition and detected genetic variants of PNPO gene, whose pathogenetic role and clinical expression remain to be established.
The goal of the present project is the characterization of the functional effects of several newly discovered mutations in PNPO gene, in order to define their pathogenicity at a molecular level. Moreover, this project will investigate the transfer mechanism of PLP from PNPO to PLP-dependent enzymes responsible for neurotransmitter production. This is an often underestimated and never fully characterized feature, which could be related to the onset of epileptic phenotypes of patients showing PNPO mutations.
Our proposed studies also comprise patients screening, aimed at expanding the clinical framework currently associated with PNPO deficiency. We will evaluate the potential involvement of PNPO gene in the pathogenesis of a wider range of generalized idiopathic epilepsies, beyond the strictly neonatal age and showing different patterns of clinical severity. This would open up new therapeutic perspectives, extending the use of pyridoxine and PLP to other types of epileptic manifestations.