ITSN1 Gene – Intersectin 1: Function, Mutations, and Disease Associations

ITSN1 encodes intersectin 1, a multidomain scaffold protein involved in clathrin-mediated endocytosis, signal transduction, and cytoskeletal organization. It contains multiple Src homology 3 (SH3) domains, a Dbl homology (DH) domain, and a pleckstrin homology (PH) domain. ITSN1 is highly expressed in the brain and plays critical roles in neuronal development, synaptic vesicle recycling, and receptor trafficking. Alternative splicing generates long and short isoforms with distinct functions. Mutations and dysregulation of ITSN1 have been implicated in neurodevelopmental disorders, including intellectual disability and autism spectrum disorder, as well as in various cancers.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Clathrin-mediated endocytosis (Reactome: R-HSA-8856828)

• Rac1 signaling pathway (Reactome: R-HSA-9013423)

• EGFR internalization and signaling (Reactome: R-HSA-177929)

Intersectin 1 (UniProt Q15811) is a 1,721-amino-acid scaffold protein with multiple functional domains: two N-terminal Eps15 homology (EH) domains, a coiled-coil region, a DH domain, a PH domain, and five SH3 domains. The long isoform (ITSN1-L) includes a C-terminal C2 domain. ITSN1 acts as a guanine nucleotide exchange factor (GEF) for Cdc42 and Rac1, regulating actin dynamics and endocytosis. It interacts with dynamin, synaptojanin, and other endocytic proteins. In neurons, ITSN1 is essential for synaptic vesicle recycling and dendritic spine morphogenesis. Post-translational modifications include phosphorylation and ubiquitination, modulating its stability and interactions.