ZC4H2 is an X-linked zinc finger protein serving as a critical co-factor for the E3 ubiquitin ligase RNF220 in neural development and synaptic function. Functionally, ZC4H2 stabilizes RNF220 and cooperates in protein ubiquitination pathways essential for neural stem cell differentiation and neuronal development 1. Mechanistically, the RNF220/ZC4H2 complex regulates spinal cord patterning by targeting transcription factors (Dbx1/2, Nkx2.2) for degradation, establishing ventral progenitor domains that generate motor neurons and interneurons 2. ZC4H2 also promotes noradrenergic neuron development through monoubiquitylation of Phox2a/Phox2b transcription factors 3, and functions as a postsynaptic regulator by modulating AMPA receptor ubiquitination and stability at excitatory synapses 4. Disease relevance: Pathogenic ZC4H2 variants cause Wieacker-Wolff syndrome (female-restricted), an X-linked neurodevelopmental disorder featuring arthrogryposis, developmental delay, hypotonia, and intellectual disability 5. ZC4H2 mutations are among the most frequent genetic causes (9.1%) of neurogenic arthrogryposis multiplex congenita 6. Clinical significance: ZC4H2 deficiency produces cognitive impairment through dysregulated excitatory synaptic transmission, potentially reversible with AMPAR antagonists, suggesting therapeutic opportunities 4.