A patient-derived mouse model reproduces molecular, neurological, and sleep symptoms of SHINE syndrome.

Abstract

SHINE syndrome is a rare neurodevelopmental disorder caused by mutations in DLG4, which encodes the postsynaptic scaffolding protein PSD-95. Key symptoms include sleep problems, hypotonia, intellectual disability, neurological disorders, and epilepsy, hence the name 'SHINE.' Here, we developed and characterized a mouse model of SHINE syndrome carrying the patient-derived DLG4V692Wfs*12/+ variant associated with a severe form of the disorder. The mutant transcript escapes nonsense-mediated decay but results in reduced PSD-95 protein expression, faithfully reproducing the molecular phenotype observed in the patient. Behavioral analyses revealed that Dlg4V692Wfs*12/+ mice recapitulate several hallmark features of SHINE syndrome, often in a sex-specific manner. Male mutants showed deficits in learning and cognitive flexibility. Dlg4V692Wfs*12/+ mice also demonstrate trends toward altered sensory processing and socialization. Male mutants exhibited an increased proportion of short sleep bouts and compensatory longer average sleep bout length, suggesting sporadic sleep reminiscent of the patient. While spontaneous seizures were not observed, future studies will test susceptibility to provoked seizures. Together, these findings establish Dlg4V692Wfs*12/+ mice as a robust and translationally relevant model that reproduces key molecular and behavioral features of SHINE syndrome. This model provides a valuable resource for elucidating the mechanisms underlying synaptic neurodevelopmental disorders and for identifying potential therapeutic strategies.