Beschreibung:
<jats:title>Abstract</jats:title><jats:p><jats:italic>SHANK2</jats:italic> mutations have been identified in individuals with neurodevelopmental disorders, including intellectual disability and autism spectrum disorders (ASD). Using CRISPR/Cas9 genome editing, we obtained SH-SY5Y cell lines with frameshift mutations on one or both <jats:italic>SHANK2</jats:italic> alleles. We investigated the effects of the different <jats:italic>SHANK2</jats:italic> mutations on cell morphology, cell proliferation and differentiation potential during early neuronal differentiation. All mutant cell lines showed impaired neuronal differentiation marker expression. Cells with bi-allelic <jats:italic>SHANK2</jats:italic> mutations revealed diminished apoptosis and increased proliferation, as well as decreased neurite outgrowth during early neuronal differentiation. Bi-allelic <jats:italic>SHANK2</jats:italic> mutations resulted in an increase in p-AKT levels, suggesting that <jats:italic>SHANK2</jats:italic> mutations impair downstream signaling of tyrosine kinase receptors. Additionally, cells with bi-allelic <jats:italic>SHANK2</jats:italic> mutations had lower amyloid precursor protein (APP) expression compared to controls, suggesting a molecular link between <jats:italic>SHANK2</jats:italic> and APP. Together, we can show that frameshift mutations on one or both <jats:italic>SHANK2</jats:italic> alleles lead to an alteration of neuronal differentiation in SH-SY5Y cells, characterized by changes in cell growth and pre- and postsynaptic protein expression. We also provide first evidence that downstream signaling of tyrosine kinase receptors and amyloid precursor protein expression are affected.</jats:p>