A zebrafish model of NEXMIF-related encephalopathy identified drivers of hyperlocomotion and provides a scalable platform for drug discovery

Functional analyses demonstrated that the upregulated genes entpd3 (Ectonucleoside Triphosphate Diphosphohydrolase 3) and ddx43 (DEAD-Box Helicase 43) act synergistically to attenuate neuronal excitability, while downregulation of kbtbd7 (Kelch repeat and BTB domain-containing protein 7) contributes directly to the hyperactive phenotype. A targeted screen of 87 natural compounds identified kahweol acetate, veratridine and rauwolscine as potent inducers of entpd3.

However, despite robust transcriptional activation, rauwolscine failed to improve behavioral outcomes, suggesting that modulation of a single target may be insufficient for phenotypic rescue. Collectively, these findings establish the first zebrafish model of NEXMIF-related encephalopathy, identify entpd3, ddx43 and kbtbd7 as key modulators of neuronal excitability, and provide a scalable platform for targeted therapeutic discovery in XLID-98.