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 seizures 1 . 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 disturbances 2,3 . 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.Correspondence should be addressed to R.O. (e-mail: ro6@columbia.edu). NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2008 December 22. Published in final edited form as:Nat Genet. 2002 March ; 30(3): 335-341. doi:10.1038/ng832. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn 1995 we mapped the ADPEAF locus to a 10-cM region on chromosome 10q24 in a single extended pedigree 2 . Linkage was subsequently reported to an overlapping interval in another large family, narrowing the minimal genetic region to approximately 3 cM, assuming the causative gene was the same 4 . Analysis of additional pedigrees confirmed the linkage but failed to narrow the region further 5-7 . To screen for disease-related mutations, we resequenced all coding-exon and bordering-intron sequences from positional candidate genes in the overlap interval in one affected individual from each of three ADPEAF pedigrees showing linkage to chromosome 10q24 (families 6610, A and B; Fig. 2) 2,7 . We then genotyped putative diseaserelated mutations in all available family members from the three linked pedigrees, all family members from two smaller families with ADPEAF (families C and D; Fig. 2) and 123 unrelated control individuals.Resequencing of LGI1 identified presumptive mutations in each of the five families with ADPEAF (Table 1 and Fig. 2). All tested affected individuals from the five families harbored a single copy of a putative disease mutation, as did all obligate carriers and individuals classified as 'unknown' who were found to carry the disease-linked haplotype (Fig. 2). Several unaffected individuals also carried the disease haplotype and presumptive mutation. Whether these individuals manifest subclinical signs of disease or have undergone recent changes in affection status is not yet known, but the results are consistent with our previous estimate of 71% disease-gene penetrance in family 6610 (ref.2).To di...

The Emerging Link Between Autoimmune Disorders and Neuropsychiatric Disease

“…Leucine-rich glioma-inactivated 1 (LGI1) is a secreted protein that interacts with presynaptic ADAM23 and postsynaptic ADAM22 to create a trans -synaptic protein complex, which also includes potassium channels and AMPA-type glutamate receptors. 29,30 Mutations in LGI1 are known to cause autosomal-dominant partial epilepsy with auditory features, 31 a syndrome characterized by temporal lobe seizures with prominent auditory hallucinations (Table 1). 32 A classic limbic encephalitis previously thought to be caused by autoantibodies recognizing voltage-gated potassium channels (VGKC) is now known to result from autoantibodies targeting LGI1.…”

Axonemal protofilament ribbons, DM10 domains, and the link to juvenile myoclonic epilepsy

“…LGI1, a leucine-rich repeat protein containing a signal sequence and extended C-terminal epitempin repeat domain of unknown function, is defective in a rare form of lateral temporal lobe epilepsy [Gu et al, 2002;Kalachikov et al, 2002].…”

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

“…2,3 Its inheritance pattern is autosomal dominant with reduced penetrance (around 70%). Mutations associated with ADLTE are found in leucine-rich, glioma inactivated 1 (LGI1 [MIM: 604619]) [4][5][6] in 30%-50% of ADLTE-affected families. 3,7,8 Other genes harboring ADLTE-causing mutations are unknown.…”

“…LGI1 is expressed mainly in neurons, particularly in the neocortex and limbic regions, 4,9 and its protein product, LGI1, is secreted. 9 LGI1 has been implicated in the transmission of K þ and AMPA synaptic currents 10,11 and in the regulation of post-natal maturation of cortical excitatory synapses and dendrite pruning.…”