Comprehensive analysis of the molecular pathogenesis of gyrate atrophy towards the rationalization and the optimization of the therapy with vitamin B6

Gyrate atrophy (GA) is a rare genetic disorder caused by mutations of ornithine aminotransferase (OAT), an enzyme requiring pyridoxal 5'-phosphate (PLP) for its function. The mechanisms of the disease have not been clarified and there is not a specific treatment strategy. The only curative treatments available are the administration of pyridoxine (PN) or a dietary restriction of arginine. Although PN treatment is widely used for many rare diseases due to deficit of PLP-enzymes, it is not clear which patients could be responsive to the therapy and how it works at molecular and cellular level. Thus, in order to foresee patient responsiveness, it is important to clarify the genotype/phenotype correlations with respect to the therapy. The first objective of this project is to acquire information on the pathological effects caused by the individual mutations associated with GA on the structure and function of OAT, and to test whether the treatment with PN can restore or at least ameliorate the function of the mutant enzymes. Moreover, with the aim of boosting the possible therapeutic efficacy of PN, we intend to test if other vitamers B6, like pyridoxal or pyridoxamine, could be more effective than PN. We will determine the most effective vitamer for each mutation and its optimal therapeutic dose. Overall, the obtained results will allow to: (i) have a detailed picture of the disease mechanisms, (ii) define suitable criteria to correlate patient genotype with PN responsiveness, thus paving the way for a patient-tailored therapeutic management of GA, (iii) unravel the basis of PN responsiveness, (ii) identify the most effective B6 vitamer to be administered to the patients, and (iv) establish a framework for investigating the pathological consequences and the responsiveness of newly-identified mutations.