Reversibility and developmental neuropathology of linear nevus sebaceous syndrome caused by dysregulation of the RAS pathway.

Linear nevus sebaceous syndrome (LNSS) is a neurocutaneous disorder caused by somatic gain-of-function mutations in KRAS or HRAS. LNSS brains have neurodevelopmental defects, including cerebral defects and epilepsy; however, its pathological mechanism and potentials for treatment are largely unclear. We show that introduction of KRAS ^G12V in the developing mouse cortex results in subcortical nodular heterotopia and enhanced excitability, recapitulating major pathological manifestations of LNSS. Moreover, we show that decreased firing frequency of inhibitory neurons without KRAS^G12V expression leads to disrupted excitation and inhibition balance. Transcriptional profiling after destabilization domain-mediated clearance of KRAS^G12V in human neural progenitors and differentiating neurons identifies reversible functional networks underlying LNSS. Neurons expressing KRAS^G12V show molecular changes associated with delayed neuronal maturation, most of which are restored by KRAS^G12V clearance. These findings provide insights into the molecular networks underlying the reversibility of some of the neuropathologies observed in LNSS caused by dysregulation of the RAS pathway. [Display omitted] • Introduction of KRAS^G12V in developing cortex recapitulates LNSS neuropathologies • Clearance of KRAS^G12V defines reversible and persistent molecular networks • Findings provide insights into pathomechanisms and potential for treatment Kim et al. establish an animal and human neural progenitor cell-based model of linear nevus sebaceous syndrome caused by mutations activating the RAS pathway. Clearance of the disease-causing protein identifies reversible functional networks. Their results provide insights into reversible networks and potential for treatment. [ABSTRACT FROM AUTHOR]