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Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features

Abstract

The epilepsies are a common, clinically heterogeneous group of disorders defined by recurrent unprovoked seizures1. Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances2,3. We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes (Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF. Previous studies have indicated that loss of both copies of LGI1 promotes glial tumor progression. We show that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies.

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Figure 1: Transcript map of the genetically defined interval for ADPEAF on chromosome 10q24.
Figure 2: Segregation of putative disease alleles in families with ADPEAF.
Figure 3: Predicted effect of ADPEAF mutations on Lgi1.
Figure 4: Aberrant LGI1 splicing in family B.
Figure 5: Analysis of Lgi1 expression in the adult mouse brain by chromogenic RNA in situ hybridization.

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Acknowledgements

This work was supported by grants from the National Institutes of Health, National Institute of Neurological Disorders and Stroke and by funds from the Columbia Genome Center. We thank A. Efstratiadis, I. Dragatsis, I. Lipkin, M. Hornig and H. Scharfman for their critical discussions and helpful suggestions; J. Ju, A.K. Tong and C. Wang for timely technical assistance; P. McCabe, C.D. McNew and S.R. Resor for family referrals and W. Jimenez for assistance with database management. This research would not have been possible without the generous participation of the families described.

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Correspondence to Ruth Ottman.

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Kalachikov, S., Evgrafov, O., Ross, B. et al. Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat Genet 30, 335–341 (2002). https://doi.org/10.1038/ng832

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