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.

/pdf/lgi-proteins-in-the-nervous-system-1icec8kkmo.pdf

LGI Proteins in the Nervous System

Epilepsy coexisting with depression

Mutations in the genes encoding Leucine Rich Repeat (LRR) containing proteins are associated with over sixty human diseases; these include high myopia, mitochondrial encephalomyopathy, and Crohn's disease. These mutations occur frequently within the LRR domains and within the regions that shield the hydrophobic core of the LRR domain. The amino acid sequences of fifty-five LRR proteins have been published. They include Nod-Like Receptors (NLRs) such as NLRP1, NLRP3, NLRP14, and Nod-2, Small Leucine Rich Repeat Proteoglycans (SLRPs) such as keratocan, lumican, fibromodulin, PRELP, biglycan, and nyctalopin, and F-box/LRR-repeat proteins such as FBXL2, FBXL4, and FBXL12. For example, 363 missense mutations have been identified. Replacement of arginine, proline, or cysteine by another amino acid, or the reverse, is frequently observed. The diverse effects of the mutations are discussed based on the known structures of LRR proteins. These mutations influence protein folding, aggregation, oligomerization, stability, protein-ligand interactions, disulfide bond formation, and glycosylation. Most of the mutations cause loss of function and a few, gain of function.

Leucine Rich Repeat Proteins: Sequences, Mutations, Structures and Diseases

https://n.neurology.org/content/neurology/62/11/2146.full.pdf

LGI1 mutations in autosomal dominant partial epilepsy with auditory features

SummaryPurpose
In relatively small series, autosomal dominant lateral temporal epilepsy (ADLTE) has been associated with leucine-rich, glioma-inactivated 1 (LGI1) mutations in about 50% of the families, this genetic heterogeneity being probably caused by differences in the clinical characteristics of the families. In this article we report the overall clinical and genetic spectrum of ADLTE in Italy with the aim to provide new insight into its nosology and genetic basis.

Methods
In a collaborative study of the Commission of Genetics of the Italian League Against Epilepsy (LICE) encompassing a 10-year period (2000–2010), we collected 33 ADLTE families, selected on the basis of the following criteria: presence of at least two members concordant for unprovoked partial seizures with prominent auditory and or aphasic symptoms, absence of any known structural brain pathology or etiology, and normal neurologic examination. The clinical, neurophysiologic, and neuroradiologic findings of all patients were analyzed and a genealogic tree was built for each pedigree. The probands' DNA was tested for LGI1 mutations by direct sequencing and, if negative, were genotyped with single-nucleotide polymorphism (SNP) array to search for disease-linked copy-number variation CNV. The disease penetrance in mutated and nonmutated families was assessed as a proportion of obligate carriers who were affected.

Key Findings
The 33 families included a total of 127 affected individuals (61 male, 66 female, 22 deceased). The age at onset ranged between 2 and 60 years (mean 18.7 years). Ninety-one patients (72%) had clear-cut focal (elementary, complex, or secondarily generalized) seizures, characterized by prominent auditory auras in 68% of the cases. Other symptoms included complex visual hallucinations, vertigo, and deja vu. Aphasic seizures, associated or not with auditory features, were observed in 20% of the cases, whereas tonic–clonic seizures occurred in 86% of the overall series. Sudden noises could precipitate the seizures in about 20% of cases. Seizures, which usually occurred at a low frequency, were promptly controlled or markedly improved by antiepileptic treatment in the majority of patients. The interictal electroencephalography (EEG) studies showed the epileptiform temporal abnormalities in 62% of cases, with a slight predominance over the left region. Magnetic resonance imaging (MRI) or computerized tomography (CT) scans were negative. LGI1 mutations (missense in nine and a microdeletion in one) were found in only 10 families (30%). The patients belonging to the mutated and not mutated groups did not differ except for penetrance estimate, which was 61.3% and 35% in the two groups, respectively (chi-square, p = 0.017). In addition, the disease risk of members of families with mutations in LGI1 was three times higher than that of members of LGI1-negative families (odds ratio [OR] 2.94, confidence interval [CI] 1.2–7.21).

Significance
A large number of ADLTE families has been collected over a 10-year period in Italy, showing a typical and homogeneous phenotype. LGI1 mutations have been found in only one third of families, clinically indistinguishable from nonmutated pedigrees. The estimate of penetrance and OR, however, demonstrates a significantly lower penetrance rate and relative disease risk in non–LGI1-mutated families compared with LGI1-mutated pedigrees, suggesting that a complex inheritance pattern may underlie a proportion of these families.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/epi.12194

Low penetrance of autosomal dominant lateral temporal epilepsy in Italian families without LGI1 mutations.

Depression is the most common comorbid condition in epilepsy, affecting 20–55% of patients (Mendez et al., 1986; Edeh & Toone 1987; Robertson et al., 1987; Baker et al., 1996; Jacoby et al., 1996; Lambert & Robertson 1999; Hesdorffer et al., 2000; Hesdorffer et al., 2006). The cause of this comorbidity is unknown. Possible explanations include psychosocial consequences of epilepsy, treatment side-effects, seizure manifestations, or common neurobiologic mechanisms. While studies have consistently shown an increased risk of depression after epilepsy onset (Edeh & Toone 1987; Jacoby et al., 1996), some data also suggest that depressed individuals have an increased risk of developing epilepsy (Forsgren & Nystrom 1990; Hesdorffer et al., 2000; Hesdorffer et al., 2006). This bidirectional relationship supports the hypothesis of overlapping mechanisms for the two disorders (Kanner 2003; Kanner 2006; LaFrance et al., 2008), which might be mediated by a shared genetic susceptibility or by common environmental risk factors.

The comorbidity of epilepsy with depression is especially striking for temporal lobe epilepsy (TLE) (Edeh & Toone 1987; Perini et al., 1996; Hesdorffer et al., 2000; Quiske et al., 2000; Piazzini et al., 2001; Gaitatzis et al., 2004), suggesting limbic system involvement for both disorders (Kanner & Balabanov 2002; Briellmann et al., 2007; Kanner 2008). So far, only one gene has been identified with a major influence on susceptibility to a form of TLE: the leucine-rich, glioma inactivated 1 gene (LGI1). Mutations in LGI1 have been identified in approximately 50% of families with autosomal dominant partial epilepsy with auditory features (ADPEAF), and have a penetrance of about 67% (Rosanoff & Ottman 2008). ADPEAF is an idiopathic focal epilepsy syndrome with auditory symptoms or receptive aphasia as major ictal manifestations (Ottman et al., 1995; Poza et al., 1999; Winawer et al., 2000; Winawer et al., 2002; Michelucci et al., 2003). These symptoms strongly suggest localization to the lateral temporal lobe, and hence the syndrome has also been called autosomal dominant lateral temporal lobe epilepsy. Psychiatric symptoms, including depression and suicide, were reported in one ADPEAF family with an LGI1 mutation (Chabrol et al., 2007).

We took advantage of this gene identification to investigate the hypothesis of a shared genetic susceptibility to epilepsy and depression. Specifically, we investigated whether mutations in LGI1, which are known to have a strong effect on the risk for epilepsy, also raise the risk for depressive symptoms.

Although the penetrance of mutations in ADPEAF families is relatively high, some family members with mutations remain unaffected with epilepsy. Hence in assessing the possible effects of LGI1 mutations on depression, we studied mutation carriers with and without epilepsy separately, to distinguish the effects of epilepsy or its treatment from those of mutations per se.

Evaluation of depression risk in LGI1 mutation carriers.

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Evaluation of depression risk in LGI1 mutation carriers.