已知富含亮氨酸的神经胶质瘤灭活蛋白1(LGI1)在常染色体显性遗传颞叶外侧癫痫(ADLTE)中起关键作用。ADLTE是一种遗传性疾病,其特征是局灶性癫痫发作,具有独特的听觉或失语症状。已经报道了Lgi1基因上的大量突变,并且被认为是ADLTE的遗传原因。我们发现了一个新的错义突变,c.152A>G(p。Asp51Gly),来自中国ADLTE患者的Lgi1,该患者表现出运动失衡和白质减少。然而,目前尚不清楚突变LGI1如何导致分子和细胞水平的白质异常.这里,我们产生了一个带有Lgi1突变的敲入小鼠。我们发现Lgi1D51G/D51G小鼠表现出受损的白质和运动协调缺陷。我们观察到Lgi1D51G/D51G小鼠在白质中显示出数量减少的成熟少突胶质细胞(OL)和缺乏OL分化。然而,Lgi1D51G/D51G小鼠的少突胶质细胞前体细胞群没有受到影响。机械上,我们发现Lgi1D51G突变导致mTOR信号传导改变,并导致Sox10水平降低.鉴于Sox10是控制OL分化的关键转录因子,我们的结果强烈提示Lgi1D51G突变可能通过抑制Sox10依赖性的OL分化和中枢神经系统髓鞘形成而导致白质异常.
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 Lgi1D51G / D51G mice exhibited impaired defective white matter and motor coordination. We observed that Lgi1D51G / 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 Lgi1D51G / D51G mice. Mechanistically, we showed that the Lgi1D51G 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 Lgi1D51G mutation may cause white matter abnormalities via inhibiting Sox10-dependent OL differentiation and myelination in the central nervous system.