A novel Lgi1 mutation causes white matter abnormalities and impairs motor coordination in mice

Abstract Leucine‐rich glioma‐inactivated protein 1 (LGI1) is known to play a key role in autosomal dominant lateral temporal lobe epilepsy (ADLTE). The ADLTE is an inherited disease characterized by focal seizures with distinctive auditory or aphasic symptoms. A large number of mutations on the Lgi1 gene have been reported and are believed to be the genetic cause for ADLTE. We identified a novel missense mutation, c.152A>G (p.Asp51Gly), on Lgi1 from a Chinese ADLTE patient who manifests locomotor imbalance and white matter reduction. However, it remains unknown how mutant LGI1 causes white matter abnormalities at molecular and cellular levels. Here, we generated a knock‐in mouse bearing this Lgi1 mutation. We found that Lgi1 D51G / D51G mice exhibited impaired defective white matter and motor coordination. We observed that Lgi1 D51G / D51G mice displayed a reduced number of mature oligodendrocytes (OLs) and deficient OL differentiation in the white matter. However, the population of oligodendrocyte precursor cells was not affected in Lgi1 D51G / D51G mice. Mechanistically, we showed that the Lgi1 D51G mutation resulted in altered mTOR signaling and led to decreased levels of Sox10. Given that Sox10 is a key transcriptional factor to control OL differentiation, our results strongly suggest that the Lgi1 D51G mutation may cause white matter abnormalities via inhibiting Sox10‐dependent OL differentiation and myelination in the central nervous system.