HECW2 is a HECT-type E3 ubiquitin ligase that functions as a critical regulator of protein stability and cellular processes. Molecularly, HECW2 mediates ubiquitination of multiple substrates including TP73, which it stabilizes to enhance TP73-dependent transcription 1. Beyond transcriptional regulation, HECW2 participates in mitotic control by regulating metaphase/anaphase transition 2. HECW2 also ubiquitinates PCNA and lamin B1, targeting them for proteasomal degradation, particularly in cells expressing lamin A mutations associated with laminopathies 3. Additionally, HECW2 mediates K48-linked ubiquitination of fibronectin in hepatic stellate cells, regulating extracellular matrix deposition during liver fibrosis 4. Clinically, HECW2 variants cause a severe neurodevelopmental disorder characterized by universal hypotonia, developmental delay/intellectual disability, and developmental language disorder (100% penetrance each) 5. Seizures occur in 61.3% of affected individuals, with additional common features including behavioral problems (88.9%), vision problems (83.9%), and motor coordination deficits (75%) 5. Pathogenic variants cluster in the C-terminal HECT domain, with four recurrent variants accounting for the majority of cases 5. Zebrafish models demonstrate that hecw2a knockdown causes early brain morphological abnormalities 6, establishing a functional link between HECW2 dysfunction and neurodevelopment.