A PATIENT-DERIVED TBR1 MUTATION IS ASSOCIATED WITH SEX-DEPENDENT CHANGES IN VASCULAR MATURATION AND MYELINATION

Autism spectrum disorder (ASD) shows marked male predominance, yet the biological basis of this sex dimorphism remains unclear. Here, we modeled a de novo TBR1 K228E mutation, identified in a male with ASD, in a mouse line to test whether this postmitotic neuronal transcription factor influences neurovascular maturation and myelination in a sex-dependent manner. Remarkably, males and females showed strikingly different outcomes. Male mutants exhibited persistent white matter abnormalities and myelin deficits. In contrast, female mutants exhibited milder structural abnormalities. Behaviorally, adult male mutants displayed increased anxiety-like behavior, while females showed minimal genotype effects. Mechanistically, males displayed prolonged vascular immaturity, with sustained claudin-5 reduction and early disruption of Reelin-dependent signaling, whereas females showed recovery by adulthood. These findings demonstrate that a patient-derived ASD mutation in a cortical transcription factor exerts pronounced sex-dependent effects on neurovascular maturation and myelination. This identifies neurovascular mechanisms as a key, previously underexplored component of sex-biased TBR1-associated ASD pathology and may help explain male vulnerability to ASD.