Article

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

ABSTRACT

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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    • "Similar clinical findings are shared by sporadic cases referred to as idiopathic partial epilepsy with auditory features (Bisulli et al., 2004a). More than 30 mutations in the leucine-rich, glioma-inactivated 1 (LGI1) gene have been associated with ADLTE, representing the genetic hallmark of this syndrome (Nobile et al., 2009). LGI1 mutations have also been found in 2 of >200 sporadic cases (Bisulli et al., 2004b; Michelucci et al., 2007). "
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    ABSTRACT: Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, headaches, intracerebral hemorrhages, and focal neurological deficits; they can also be clinically silent and occur as a sporadic or an autosomal dominant condition. Three genes have been identified as causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3, mapping, respectively, on chromosomes 7q, 7p, and 3q. Here, we report an Italian family affected by CCM due to a MGC4607 gene mutation, on exon 4. All the affected subjects suffered from seizures, and some of them underwent surgery for removal of a cavernous angioma. Brain MRI showed multiple lesions consistent with CCMs in all patients. Spinal and cutaneous cavernous angiomas were present too. This report underlines the need for a careful interdisciplinarity among neurologists, neuroradiologists, neurosurgeons, geneticists, ophthalmologists, and dermatologists for a total evaluation of the different manifestations of familial CCM. This points out that only referral centers are organized to offer a multidisciplinary management of this disease.
    Full-text · Article · Apr 2015 · Journal of Molecular Neuroscience
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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.
    Full-text · Article · Oct 2014 · Brain
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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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