A novel loss-of-function LGI1 mutation linked to autosomal dominant lateral temporal epilepsy.

BACKGROUND: Mutations responsible for autosomal dominant lateral temporal epilepsy have been found in the leucine-rich, glioma-inactivated 1 (LGI1) gene. OBJECTIVES: To describe the clinical and genetic findings in a family with autosomal dominant lateral temporal epilepsy and to determine the functional effects of a novel LGI1 mutation in culture cells. DESIGN: Clinical, genetic, and functional investigations. SETTING: University hospital and laboratory. PATIENTS: An Italian family with autosomal dominant lateral temporal epilepsy. MAIN OUTCOME MEASURE: Mutation analysis. RESULTS: A novel LGI1 mutation, c.365T>A (Ile122Lys), segregating with the disease was identified. The mutant Lgi1 protein was not secreted by culture cells. CONCLUSION: Our data provide further evidence that mutations in LGI1 hamper secretion of the Lgi1 protein, thereby precluding its normal function.

Analysis of LGI1 promoter sequence, PDYN and GABBR1 polymorphisms in sporadic and familial lateral temporal lobe epilepsy.

Autosomal dominant lateral temporal epilepsy (ADTLE) is a genetically transmitted epileptic syndrome characterized by focal seizures with predominant auditory symptoms likely originating from the lateral region of the temporal lobe. Mutations in coding region or exon splice sites of the leucine-rich, glioma-inactivated 1 (LGI1) gene account for about 50% of ADLTE families. De novo LGI1 mutations of the same kind have also been found in about 2.5% of non-familial cases with idiopathic partial epilepsy with auditory features (IPEAF). In both conditions, mutations in the LGI1 promoter region have not been reported. We sequenced the minimal promoter region of LGI1 in the probands of 16 ADLTE families and in 104 sporadic IPEAF patients and no mutations clearly linked to the disease were found. However, two polymorphisms, -500G>A and -507G>A, with potential functional implications were identified and analysed in the cohort of sporadic IPEAF patients but their frequencies did not differ from those found in a control population of similar age, gender and geographic origin. We also analysed in our study population the GABA(B) receptor 1 c.1465G>A and the prodynorphin promoter 68-bp repeat polymorphisms, previously associated with temporal lobe epilepsy. None of these polymorphisms showed a significant association with IPEAF, whereas a tendency towards association with the prodynorphin low expression (L) alleles was found in the small group of ADLTE index cases, in agreement with previous studies suggesting that this polymorphism is a susceptibility factor in familial forms of temporal lobe epilepsy.