Evaluation of depression risk in <i>LGI1</i> mutation carriers

Heiman, Gary A.; Kamberakis, K.; Gill, Richard; Kalachikov, Sergey; Pedley, Timothy A.; Hauser, W. Allen; Ottman, Ruth

doi:10.1111/j.1528-1167.2010.02677.x

Cited by 23 publications

(18 citation statements)

References 42 publications

(57 reference statements)

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“…ADPEAF mutations have begun to be examined in the context of other neurological diseases. LGI1 mutations do not appear to affect depression independently of epilepsy (Heiman et al, 2010). The LGI1 mutation in one ADPEAF family has been correlated with hyperactivity (Berghuis et al, 2013), and it will be important to determine if LGI1 mutations impact other diseases of synaptic connectivity.…”

Section: Lgi1 Mutations In Adpeafmentioning

confidence: 99%

LGI Proteins in the Nervous System

et al. 2013

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The development and function of the vertebrate nervous system depend on specific interactions between different cell types. Two examples of such interactions are synaptic transmission and myelination. LGI1-4 (leucine-rich glioma inactivated proteins) play important roles in these processes. They are secreted proteins consisting of an LRR (leucine-rich repeat) domain and a so-called epilepsy-associated or EPTP (epitempin) 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 ADLTE (autosomal dominant lateral temporal (lobe) epilepsy) also referred to as ADPEAF (autosomal dominant partial epilepsy with auditory features). LGI1 protein appears to act at synapses and antibodies against LGI1 may cause the autoimmune disorder limbic encephalitis. A similar function in synaptic remodelling 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 towards understanding their functions.

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Section: Lgi1 Mutations In Adpeafmentioning

confidence: 99%

LGI Proteins in the Nervous System

et al. 2013

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“…For our previously reported families, [2][3][4]13,16 we obtained this information directly from our existing database. For families reported by others, we abstracted the clinical information from published reports.…”

Section: Methods Adpeaf Families Molecular and Clinical In-mentioning

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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“…1,2 Mutations in the leucine rich, glioma inactivated 1 (LGI1) gene are responsible for ADLTE in up to 50% of the families. 5,6 We report the first genomic microdeletion involving LGI1 identified in an ADLTE family by high-density single nucleotide polymorphism (SNP) array copy number variation (CNV) analysis. 5,6 We report the first genomic microdeletion involving LGI1 identified in an ADLTE family by high-density single nucleotide polymorphism (SNP) array copy number variation (CNV) analysis.…”

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confidence: 99%