4.7 Article

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

Journal

FASEB JOURNAL
Volume 36, Issue 3, Pages -

Publisher

WILEY
DOI: 10.1096/fj.202101652R

Keywords

LGI1; myelination; oligodendrocyte differentiation; Sox10; white matter

Funding

  1. National Natural Science Foundation of China [91849112, 31571060]
  2. Natural Science Foundation of Jiangsu Province [BE2019707, BK20201255]
  3. Fundamental Research Funds for the Central Universities [0903-14380029]

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Leucine-rich glioma-inactivated protein 1 (LGI1) plays a key role in autosomal dominant lateral temporal lobe epilepsy (ADLTE). A novel mutation on the Lgi1 gene was identified, which may cause white matter abnormalities by inhibiting Sox10-dependent oligodendrocyte differentiation and myelination in the central nervous system.
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.

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