MPDZ (multiple PDZ domain crumbs cell polarity complex component) is a scaffold protein essential for cell polarity and neural development. It functions as a member of the NMDAR signaling complex involved in AMPAR potentiation and synaptic plasticity in excitatory synapses 12. MPDZ localizes to apical cell junctions and tight junctions, where it directly binds to DAPLE via its PDZ3 domain to promote apical cell constriction during neurulation 3. Biallelic MPDZ mutations cause autosomal recessive congenital hydrocephalus with variable penetrance 4. The condition arises from impaired apical constriction and neural tube closure during early neurodevelopment 3. MPDZ-related disease presents as clinically heterogeneous, with hydrocephalus, vision impairment, hearing impairment, and cardiovascular anomalies occurring most frequently 5. Novel phenotypes include spasticity and complex syndromic features encompassing central and non-central nervous system malformations, including cardiac defects and ocular abnormalities 67. Beyond congenital disease, MPDZ exhibits oncogenic properties in cancer contexts. In colorectal cancer, elevated MPDZ correlates with poor prognosis and metastatic potential through YAP1 phosphorylation regulation and immune evasion 8. Conversely, MPDZ is downregulated in hepatocellular carcinoma and associates with worse outcomes through ferroptosis and metabolic pathway disruption 9.