<i>LGI1</i>mutations in autosomal dominant and sporadic lateral temporal epilepsy

Nobile, Carlo; Michelucci, Roberto; Andreazza, Simonetta; Pasini, Elena; Tosatto, Silvio C. E.; Striano, Pasquale

doi:10.1002/humu.20925

Cited by 142 publications

(128 citation statements)

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“…Also, uncertain is how LGI1 835delC functions in a dominant negative manner. Alternatively, another group suggests a loss of function mechanism based on the genetic facts that various types of mutations are associated with a rather homogenous phenotype (7). Phenotypes of LGI1 gene-targeted mice, increased seizure susceptibility in heterozygous LGI1 +/− mice and lethal epileptic seizures in homozygous LGI1 −/− mice provide supportive evidence for the haploinsufficiency mechanism of ADPEAF mutations in human; ADPEAF mutations perturb LGI1 secretion and reduce the LGI1-mediated transsynaptic connection between ADAM22 and ADAM23, leading to abnormal synaptic transmission and epilepsy.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in LGI1 are linked to autosomal dominant partial epilepsy with auditory features (ADPEAF, also known as autosomal dominant lateral temporal lobe epilepsy [ADLTE]) (3)(4)(5), which is an inherited epileptic syndrome characterized by partial seizures with acoustic or visual hallucinations. So far, 25 LGI1 mutations have been described in familial ADPEAF patients and sporadic cases (7). Interestingly, at least six tested ADPEAF mutations all abolish LGI1 secretion (6,8).…”

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confidence: 99%

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Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy

Fukata¹,

Lovero

Iwanaga³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

295

392

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Epilepsy is a devastating and poorly understood disease. Mutations in a secreted neuronal protein, leucine-rich glioma inactivated 1 (LGI1), were reported in patients with an inherited form of human epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF). Here, we report an essential role of LGI1 as an antiepileptogenic ligand. We find that loss of LGI1 in mice (LGI1 −/− ) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3. Moreover, heterozygous mice for the LGI1 mutation (LGI1 +/− ) show lowered seizure thresholds. Extracellularly secreted LGI1 links two epilepsy-related receptors, ADAM22 and ADAM23, in the brain and organizes a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus. Thus, LGI1 may serve as a major determinant of brain excitation, and the LGI1 gene-targeted mouse provides a good model for human epilepsy.A ffecting 1-2% of the population, epilepsy is one of the most common neurological disorders. Epilepsy is characterized by recurrent unprovoked seizures and is caused by disturbances in the delicate balance between excitation and inhibition in neural circuits (1, 2). Recent human genetic studies have established the channelopathy concept for idiopathic (inherited) epilepsies: Many of the genes whose mutations cause human epilepsy encode ion channel subunits (1, 2). Examples include voltagegated ion channels (K + , Na + , Ca 2+ , and Cl -channels) and ligandgated ion channels (nicotinic acetylcholine and GABA A receptors), which regulate neuronal excitability.Leucine-rich glioma inactivated 1 (LGI1) is a unique human epilepsy-related gene in that it does not encode an ion channel subunit (3-5), but is a neuronal secreted protein (6). Mutations in LGI1 are linked to autosomal dominant partial epilepsy with auditory features (ADPEAF, also known as autosomal dominant lateral temporal lobe epilepsy [ADLTE]) (3-5), which is an inherited epileptic syndrome characterized by partial seizures with acoustic or visual hallucinations. So far, 25 LGI1 mutations have been described in familial ADPEAF patients and sporadic cases (7). Interestingly, at least six tested ADPEAF mutations all abolish LGI1 secretion (6,8).Recent proteomic analysis identified LGI1 as a subunit of presynaptic Kv 1 (shaker type)-voltage gated potassium channels (9). It was shown that LGI1 selectively prevents inactivation of the Kv 1 channel mediated by a cytoplasmic regulatory protein, Kvβ. Because LGI1 is a secreted protein, it remains unclear how LGI1 modulates a cytosolic potassium channel mechanism. LGI1 was also isolated from the brain as a component of a protein complex mediated by PSD-95, a representative postsynaptic scaffolding protein.LGI1 functions as a ligand for the epilepsy-related ADAM22 transmembrane protein, which is anchored by PS...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy

Fukata¹,

Lovero

Iwanaga³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

295

392

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“…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.…”

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confidence: 99%

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

Dazzo

Fanciulli²,

Serioli

et al. 2015

The American Journal of Human Genetics

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106

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Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain.Temporal-lobe epilepsy is the most common type of focal epilepsy. It is sometimes associated with structural brain lesions, but genetic forms have also been described. Familial temporal-lobe epilepsy comprises two genetically distinct syndromes: familial mesial temporal-lobe epilepsy (FMTLE [MIM: 611630]) 1 and autosomal-dominant lateral temporal epilepsy (ADLTE [MIM: 600512]), also named autosomal-dominant partial epilepsy with auditory features (ADPEAF). 2 ADLTE is a well-defined epileptic syndrome clinically characterized by focal seizures with prominent auditory and/or aphasic symptoms, normal brain MRI, and relatively benign evolution. 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]) 4-6 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. 12 However, it is not known which of these functions underlies ADLTE. Identification of additional genes whose mutations cause ADLTE will help to clarify the pathoge...

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“…7,8,10 -15 Missense and truncation mutations have been found in both LRR and EPTP domains. Although previous studies have reported that pathogenic LGI1 mutations are uniformly distributed across the gene, 8 none has used a quantitative approach to assess mutation clustering or investigated genotype-phenotype correlations in detail. Establishment of genotype-phenotype associations has the potential to elucidate the biologic pathways involving LGI1, including the mechanisms leading to ADPEAF symptoms.…”

mentioning

confidence: 99%

“…8,9 To date, 33 unique LGI1 mutations have been reported in ADPEAF families (n ϭ 36) and sporadic patients with idiopathic focal epilepsy with auditory symptoms (n ϭ 2). 7,8,10 -15 Missense and truncation mutations have been found in both LRR and EPTP domains.…”

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confidence: 99%

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

Ho¹,

Ionita‐Laza²,

Ottman³

2012

Neurology

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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 ϭ 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 ϭ 0.018). Conclusion:The LRR region of the LGI1 gene is likely to play a major role in pathogenesis of ADPEAF. Neurology Autosomal dominant partial epilepsy with auditory features (ADPEAF) (OMIM 600512) is an idiopathic focal epilepsy syndrome with auditory symptoms or receptive aphasia as a prominent ictal manifestation.1-3 These symptoms strongly suggest localization to the lateral temporal lobe; hence, the syndrome is also called autosomal dominant lateral temporal lobe epilepsy. A substantial proportion (approximately 50%) of affected families have mutations in the leucine-rich, glioma inactivated 1 (LGI1) gene, 4 -6 with an average penetrance of 67%. 7LGI1 encodes a secreted protein, Lgi1, with 2 major domains: an N-terminal leucine-rich repeat (LRR) domain containing 4 LRRs flanked by 2 conserved cysteine-rich regions, and a C-terminal epitempin (EPTP) domain containing 7 EPTP repeats. 8,9 To date, 33 unique LGI1 mutations have been reported in ADPEAF families (n ϭ 36) and sporadic patients with idiopathic focal epilepsy with auditory symptoms (n ϭ 2). 7,8,10 -15 Missense and truncation mutations have been found in both LRR and EPTP domains. Although previous studies have reported that pathogenic LGI1 mutations are uniformly distributed across the gene, 8 none has used a quantitative approach to assess mutation clustering or investigated genotype-phenotype correlations in detail. Establishment of genotype-phenotype associations has the potential to elucidate the biologic pathways involving LGI1, including the mechanisms leading to ADPEAF symptoms.

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LGI1mutations in autosomal dominant and sporadic lateral temporal epilepsy

Cited by 142 publications

References 53 publications

Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy

Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

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

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