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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    • "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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    • "In contrast to wild-type LGI1 protein, certain mutant LGI proteins that cause ADPEAF in patients could not reduce Kv1.1 inactivation (Schulte et al., 2006). Interestingly, these same mutant LGI proteins are not secreted (Senechal et al., 2005; Sirerol-Piquer et al., 2006; Nobile et al., 2009) suggesting that LGI1 needs to be secreted prior to having an effect on channel inactivation. Since the LRR domains of LGI proteins are very homologous to the Slit proteins, they might have similar functions. "
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    ABSTRACT: The development and function of the vertebrate nervous system depends on specific interactions between different cell types. Two examples of such interactions are synaptic transmission and myelination. Leucine-rich Glioma Inactivated proteins (LGI1-4) play important roles in these processes. They are secreted proteins consisting of a Leucine-rich repeat (LRR) domain and a so-called epilepsy associated or epitempin (EPTP) domain. Both domains are thought to function in protein-protein interactions. The first LGI gene to be identified, LGI1, was found at a chromosomal translocation breakpoint in a glioma cell line. It was subsequently found mutated in Autosomal Dominant Lateral Temporal (lobe) Epilepsy (ADLTE) also referred to as Autosomal Dominant Partial Epilepsy with Auditory Features (ADPEAF). LGI1 protein appears to act at synapses and antibodies against LGI1 may cause the autoimmune disorder limbic encephalitis. A similar function in synaptic remodeling has been suggested for LGI2, which is mutated in canine Benign Familial Juvenile Epilepsy. LGI4 is required for proliferation of glia in the peripheral nervous system and binds to a neuronal receptor, ADAM22, to foster ensheathment and myelination of axons by Schwann cells. Thus, LGI proteins play crucial roles in nervous system development and function and their study is highly important, both to understand their biological functions and for their therapeutic potential. Here we review our current knowledge about this important family of proteins, and the progress made toward understanding their functions.
    ASN Neuro 05/2013; 5(3). DOI:10.1042/AN20120095 · 4.02 Impact Factor
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