Identification of neuronal alterations underlying SHANK3 mutations and their rescue by genetic/pharmacological therapies in animal models and patients’ derived iPS cells

The 22q13 deletion syndrome is a genetic disease orphan of cure which cause a sever form of mental retardation and autism. The syndrome is also characterized by neonatal hypotonia, global developmental delay, absent to severely delayed speech, and minor dysmorphic features. The increasing number of patients being reported supports the hypothesis that this syndrome may be a common source of mental retardation. However, this genetic condition remains under-diagnosed due to failure to detect the 22q13 deletion in routine chromosome analysis and to recognize the phenotype on clinical examination. Lack of one copy of the SHANK3/PROSAP2 gene, encoding a structural protein located in the synapses of the human nervous system and involved in dendritic spines formation, is very likely the cause of the major neurological features associated with the deletion 22q13 syndrome. It has also been clearly demonstrate that mutation of SHANK3/PROSAP2 is associated to mental retardation and autism. The project aims to characterize the role of SHANK3 in the correct functioning of brain synapses. We will apply complementary techniques using also animal models and to be closer to the human pathology we will establish and differentiate to neurons human pluripotent cells from patients affected by the 22q13 deletion syndrome and age-matched healthy individuals in order to further clarify the neurons alterations underlying the syndrome. All these experimental models will be tested for pharmacological and genetic rescue of the identified alterations.