THE ROLE OF SHANK3/PROSAP2 IN THE NEUROLOGICAL SYMPTOMS OF PATIENTS AFFECTED BY THE 22q13 DELETION SYNDROME

The 22q13 deletion syndrome is characterized by neonatal hypotonia, global developmental delay, absent to severely delayed speech, mild mental retardation, autistic-like behavior 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 22qter deletion in routine chromosome analysis and to recognize the phenotype on clinical examination. As a consequence, its incidence is not yet established. 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. This is strongly supported by the observation that all cases analyzed showed a deletion of SHANK3 and recently by the identification of a recurrent breakpoint within the SHANK3 gene in affected subjects. The Shank proteins are large scaffold proteins with a still incompletely understood role in synapse function. Recently, we and others have detected tissue-specific methylation of the SHANK3 gene indicating a possible tissue-specific regulation of SHANK3 expression by DNA methylation. The possibility that SHANK3 expression might be regulated by epigenetic mechanisms, such as DNA methylation, is very intriguing and suggests that SHANK3 expression could be modulated pharmacologically. With this project we aim to analyze with molecular cytogenetic techniques 22q13 deletion syndrome subjects, to characterize tissue specific methylation of SHANK genes, to investigate if DNA methylation regulates SHANK3 tissue-specific expression and to characterize the role of SHANK3 in brain synapse formation and function.