Loss of function variants in <i>TMPRSS7</i> linked to a neurodevelopmental disorder disrupt synaptic function

The molecular etiology of more than half of neurodevelopment disorders remains unknown. In this study, we identified recessive variants in the TMPRSS7 gene in a fetus from a non-consanguineous Chinese family with a history of recurrent central nervous system (CNS) malformations, as the likely genetic cause of a neurodevelopmental disorder. TMPRSS7 encodes matriptase-3, a type II transmembrane serine protease (TTSP) that becomes active when its catalytic domain is released outside the cell. During the proteolytic process, the canonical RV(I)V(I)G motif is cleaved, converting the inactive single-chain zymogen into its active form. This activation is closely temporally coupled with TTSPs shedding and ultimately leads to the release of the catalytic domain into the extracellular space to exert its function. The patient carrying compound heterozygous variants in the TMPRSS7 gene, p.R479H and p.S685Kfs*26, exhibited impaired synthesis of the matriptase-3 protease zymogen and defective shedding of the functional serine protease domain. Tmprss7 homozygous knockout (KO) mice exhibited dysregulated synaptic dendritic spine density, function, and dendritic elongation in the cerebral cortex and hippocampus. In addition, the KO animals displayed neurobehavioral deficits, including impairments in spatial learning, anxiety-like behavior, and a reduced preference for social novelty. Multi-omics analysis discovered enrichment of pathways related to synaptic signaling disruptions in both the cerebral cortex and hippocampus. Collectively, our findings identify TMPRSS7 as a candidate gene essential for normal neurodevelopment, highlighting its potential role in the molecular pathogenesis of neurodevelopmental disorders.