Domain-dependent clustering and genotype-phenotype analysis of LGI1 mutations in ADPEAF.

Abstract:

OBJECTIVE:In families with autosomal dominant partial epilepsy with auditory features (ADPEAF) with mutations in the LGI1 gene, we evaluated clustering of mutations within the gene and associations of penetrance and phenotypic features with mutation location and predicted effect (truncation or missense). METHODS:We abstracted clinical and molecular information from the literature for all 36 previously published ADPEAF families with LGI1 mutations. We used a sliding window approach to analyze mutation clustering within the gene. Each mutation was mapped to one of the gene's 2 major functional domains, N-terminal leucine-rich repeats (LRRs) and C-terminal epitempin (EPTP) repeats, and classified according to predicted effect on the encoded protein (truncation vs missense). Analyses of phenotypic features (age at onset and occurrence of auditory symptoms) in relation to mutation site and predicted effect included 160 patients with idiopathic focal unprovoked seizures from the 36 families. RESULTS:ADPEAF-causing mutations clustered significantly in the LRR domain (exons 3-5) of LGI1 (p = 0.026). Auditory symptoms were less frequent in individuals with truncation mutations in the EPTP domain than in those with other mutation type/domain combinations (58% vs 80%, p = 0.018). CONCLUSION:The LRR region of the LGI1 gene is likely to play a major role in pathogenesis of ADPEAF.

journal_name

Neurology

journal_title

Neurology

authors

Ho YY,Ionita-Laza I,Ottman R

doi

10.1212/WNL.0b013e318247ccbf

subject

Has Abstract

pub_date

2012-02-21 00:00:00

pages

563-8

issue

8

eissn

0028-3878

issn

1526-632X

pii

WNL.0b013e318247ccbf

journal_volume

78

pub_type

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