MOLECULAR GENETICS OF AUTISTIC DISORDER: FUNCTIONAL CHARACTERIZATION OF VULNERABILITY CONFERRED BY REELIN GENE ALLELES AND IDENTIFICATION OF ADDITIONAL GENES INVOLVED IN THE DISEASE

Autism is a severe neuropsichiatric disorder of childhood, whose incidence is apparently on the rise. Current pathogenetic hypotheses point toward a limited number of predisposing genetic mutations and important gene-environment interactions. We have recently identified genetic variants predisposing to the disease in the DNA encoding Reelin, a protein critical to the development of the nervous system. We have also discovered that Reelin exerts an enzymatic activity which is potently inhibited by organophosphates, widely used as pesticides and insecticides. These predisposing genetic variants appear characterized by reduced production of Reelin protein. Therefore, within the framework of an interactive gene-environment model, individuals carrying these reelin gene variants could be genetically at risk, if prenatally exposed to low but pharmacologically-active doses of organophosphates, to undergo altered neuronal migration later resulting in autism. The current project is aimed at reaching three goals within the next 2 years: (1) neuroanatomical and behavioral validation of this interactive model, prenatally exposing mice spontaneously producing 50% lower Reelin protein amounts to organophosphates ("animal model"); (2) psychological testing of individuals carrying predisposing reelin gene variants to assess whether they display reduced social skills, characteristic of the autism-spectrum personality (“unaffected carriers”); (3) search for mutations in other genes producing proteins functionally related to Reelin in the nervous system and possibly causing or predisposing to the disease (“genetic screening”). The potential validation of our model could undoubtedly yield preventive measures in regard to the environmental use of organophosphates, and possibly to earlier and more reliable diagnoses, and to novel therapeutic strategies.