Prof. Enza Maria Valente
The research activity of the Unit, in close interaction with the diagnostic cytogenetic and molecular genetic lab, aims at characterizing the genetic basis of rare neurological diseases, including both those with pediatric and with adult onset. This translational approach is patient-centered and involves multiple steps: 1) deep phenotyping (clinical, neuroradiological and instrumental) of patients with rare diseases suspected of having a genetic (monogenic) origin; 2) identification of the genetic basis of the disease, by searching for mutations in known causative genes and, if negative, for novel genetic determinants, by means of whole exome sequencing or whole genome sequencing and complementary techniques (MLPA, SNP-array etc); 3) assessment of the impact of identified genetic variants using bioinformatic approaches and functional assays in vitro; 4) identification and functional characterization of unconventional “cryptic” variants in known genes, including variants within intronic or regulatory regions which may affect the splicing or expression of the gene; 5) characterization of novel disease genes by means of functional studies in vitro, using engineered cell lines as well as patient-derived cellular models (induced pluripotent stem cells differentiated into neural stem cells and mature neurons), through an array of technologies, including immunofluorescence and confocal microscopy, real-time PCR, western blot, transcriptomic studies, co-immunoprecipitation and AlphaLisa assays; 6) gene-phenotype and genotype-phenotype correlates, description of the natural history and identification of prognostic indicators for rare neurogenetic diseases.
The close interaction with the diagnostic lab allows the possibility to study large cohorts of patients with rare neurogenetic diseases, to define the mutational spectrum and associated phenotypes of disease-genes and to select homogeneous populations of patients negative for known genetic defects to prompt the discovery and characterization of novel genes. The major pediatric areas of research focus on inherited neurodevelopmental defects, congenital brain malformations (with particular interest for cerebellar malformations), congenital and pediatric ataxias and primary ciliopathies; regarding adult-onset neurogenetic disorders, the group mainly focuses on monogenic forms of Parkinson disease, dystonia and other movement disorders. These activities are carried out as part of research projects funded by various entities, such as the Ministry of Health (Ricerca Corrente, Ricerca Finalizzata, ERANET project), CARIPLO Foundation, Telethon Foundation Italy and Mariani Foundation for Pediatric Neurology. The PI is member of the Scientific Committee of the Global Parkinson’s Genetics Program (GP2), a five-year worldwide program aimed at further understanding the genetic architecture of Parkinson’s disease, funded by the Michael J Fox Foundation in the frame of the Aligning Science Across Parkinson’s (ASAP) initiative.