LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy

Istituto di Neuroscienze del CNR, Sezione di Padova, Dipartimento di Scienze Biomediche Sperimentali, Università di Padova, Padova, Italy.
Human Mutation (Impact Factor: 5.14). 04/2009; 30(4):530-6. DOI: 10.1002/humu.20925
Source: PubMed


Autosomal dominant lateral temporal epilepsy (ADLTE) or autosomal dominant partial epilepsy with auditory features (ADPEAF) is an inherited epileptic syndrome with onset in childhood/adolescence and benign evolution. The hallmark of the syndrome consists of typical auditory auras or ictal aphasia in most affected family members. ADTLE/ADPEAF is associated in about half of the families with mutations of the leucine-rich, glioma-inactivated 1 (LGI1) gene. In addition, de novo LGI1 mutations are found in about 2% of sporadic cases with idiopathic partial epilepsy with auditory features, who are clinically similar to the majority of patients with ADLTE/ADPEAF but have no family history. Twenty-five LGI1 mutations have been described in familial and sporadic lateral temporal epilepsy patients. The mutations are distributed throughout the gene and are mostly missense mutations occurring in both the N-terminal leucine rich repeat (LRR) and C-terminal EPTP (beta propeller) protein domains. We show a tridimensional model of the LRR protein region that allows missense mutations of this region to be divided into two distinct groups: structural and functional mutations. Frameshift, nonsense and splice site point mutations have also been reported that result in protein truncation or internal deletion. The various types of mutations are associated with a rather homogeneous phenotype, and no obvious genotype-phenotype correlation can be identified. Both truncating and missense mutations appear to prevent secretion of mutant proteins, suggesting a loss of function effect of mutations. The function of LGI1 is unclear. Several molecular mechanisms possibly leading to lateral temporal epilepsy are illustrated and briefly discussed.

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Available from: Simonetta Andreazza, Mar 20, 2015
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    • "One-third of the 39 published ADEAF-causing mutations result in a premature stop codon, which causes haploinsufficiency. Numerous missense mutations prevent LGI1 secretion from transfected cells (Senechal et al., 2005; Sirerol-Piquer et al., 2006; Chabrol et al., 2007; Striano et al., 2008; de Bellescize et al., 2009; Nobile et al., 2009; Di Bonaventura et al., 2011; Leonardi et al., 2011; Fanciulli et al., 2012; Sadleir et al., 2013; Lee et al., 2014). Other pathogenic mutations may impair LGI1 interactions with protein partners rather than suppressing protein secretion (Striano et al., 2011). "
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    ABSTRACT: Leucin-rich, glioma inactivated 1 (LGI1) is a secreted protein linked to human seizures of both genetic and autoimmune aetiology. Mutations in the LGI1 gene are responsible for autosomal dominant temporal lobe epilepsy with auditory features, whereas LGI1 autoantibodies are involved in limbic encephalitis, an acquired epileptic disorder associated with cognitive impairment. We and others previously reported that Lgi1-deficient mice have early-onset spontaneous seizures leading to premature death at 2–3 weeks of age. Yet, where and when Lgi1 deficiency causes epilepsy remains unknown. To address these questions, we generated Lgi1 conditional knockout (cKO) mice using a set of universal Cre-driver mouse lines. Selective deletion of Lgi1 was achieved in glutamatergic pyramidal neurons during embryonic (Emx1-Lgi1cKO) or late postnatal (CaMKIIα-Lgi1cKO) developmental stages, or in gamma amino butyric acidergic (GABAergic) parvalbumin interneurons (PV-Lgi1cKO). Emx1-Lgi1cKO mice displayed early-onset and lethal seizures, whereas CaMKIIα-Lgi1cKO mice presented late-onset occasional seizures associated with variable reduced lifespan. In contrast, neither spontaneous seizures nor increased seizure susceptibility to convulsant were observed when Lgi1 was deleted in parvalbumin interneurons. Together, these data showed that LGI1 depletion restricted to pyramidal cells is sufficient to generate seizures, whereas seizure thresholds were unchanged after depletion in gamma amino butyric acidergic parvalbumin interneurons. We suggest that LGI1 secreted from excitatory neurons, but not parvalbumin inhibitory neurons, makes a major contribution to the pathogenesis of LGI1-related epilepsies. Our data further indicate that LGI1 is required from embryogenesis to adulthood to achieve proper circuit functioning.
    Brain 10/2014; 137(11):awu259. DOI:10.1093/brain/awu259 · 9.20 Impact Factor
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    • "This is consistent with the idea that the phenotype of Lgi1 L385R/+ rats is derived from the loss of functional LGI1 protein rather than that of mRNA (Baulac et al., 2012). Most patients with ADLTE have mutations in the LGI1 gene that impair protein secretion (Senechal et al., 2005; Michelucci et al., 2009; Nobile et al., 2009; Di Bonaventura et al., 2011). Recently, Striano et al. (2011) reported a family with ADLTE with a novel LGI1 mutation (R407C) that did not disturb LGI extracellular protein secretion; the R407C LGI1 mutation, however, disrupts interactions with its target proteins (Striano et al., 2011). "
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    ABSTRACT: Mutations in the leucine-rich, glioma inactivated 1 (LGI1) gene have been identified in patients with autosomal dominant lateral temporal lobe epilepsy (ADLTE). We previously reported that Lgi1 mutant rats, carrying a missense mutation (L385R) generated by gene-driven N-ethyl-N-nitrosourea (ENU) mutagenesis, showed generalized tonic-clonic seizures (GTCS) in response to acoustic stimuli. In the present study, we assessed clinically-relevant features of Lgi1 heterozygous mutant rats (Lgi1(L385R/+)) as an animal model of ADLTE. First, to explore the focus of the audiogenic seizures, we performed electroencephalography (EEG) and brain Fos immunohistochemistry in Lgi1(L385R/+) and wild type rats. EEG showed unique seizure patterns (e.g., bilateral rhythmic spikes) in Lgi1(L385R/+) rats with GTCS. An elevated level of Fos expression indicated greater neural excitability to acoustic stimuli in Lgi1(L385R/+) rats, especially in the temporal lobe, thalamus and subthalamic nucleus. Finally, microarray analysis revealed a number of differentially expressed genes that may be involved in epilepsy. These results suggest that Lgi1(L385R/+) rats are useful as an animal model of human ADLTE.
    Neuroscience Research 01/2014; 80(1). DOI:10.1016/j.neures.2013.12.008 · 1.94 Impact Factor
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    • "It is highly expressed in the hippocampus and neocortex, but present in varying degrees throughout the CNS. In vitro studies and animal models have mapped a variable pattern of expression and suggested a key migratory role of LGI1 in normal brain development, as well as regulating synaptic transmission (Nobile et al., 2009). One study of a family affected by ADTLE revealed lateral temporal lobe dysgenesis in 10/19 family members with a confirmed LGI1 point mutation, while another study using diffusion-tensor imaging revealed focally elevated fractional anisotropy (FA) in the left middle temporal gyrus in eight patients with LG1 mutations when compared with 24 controls (Kobayashi et al., 2003; Tessa et al., 2007). "
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    ABSTRACT: Limbic encephalitis involving anti-voltage-gated potassium channel antibodies (VGKC-LE) has become increasingly recognised, with seizures and psychotic features, such as hallucinations being typical clinical manifestations. Though the literature supports auditory hallucinations as ictal phenomena, there are no reported cases of these hallucinations correlating with electrographic seizure for this disease entity. Early recognition of auditory hallucinations as seizures could alter treatment and subsequently affect short-term outcomes in these patients. We report the case of a patient with auditory hallucinations and progressive cognitive decline, as well as serological evidence of VGKC antibodies, in whom ictal hallucinations were identified by continuous video-EEG monitoring. This case highlights the subtlety of this entity, in both clinical and electrographic detection. [Published with video sequences].
    Epileptic disorders: international epilepsy journal with videotape 12/2013; 15(4):433-6. DOI:10.1684/epd.2013.0623 · 0.95 Impact Factor
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