Disease relevance of LGI1

• Progressive loss of LGI1 expression has been associated with the development of high grade gliomas [1].
• Mutations in LGI1 (leucine-rich, glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF) [2].
• LGI1 mutations in temporal lobe epilepsies [2].
• In addition, decreases in LGI1 expression are observed in glioblastoma patient samples and glioblastoma cell lines [3].
• A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors [4].
• Our data indicate that LGI1 is a secreted protein and suggest that LGI1-related epilepsy results from a loss of function [5].

Psychiatry related information on LGI1

• This study explored the effect of expressive physical touch with verbalization (EPT/V) on anxiety and dysfunctional behavior in patients with dementia using a one group repeated measures design [6].

High impact information on LGI1

• We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes (Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF [7].
• Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies [7].
• We show that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy [7].
• Here, we show that Kv1.1-containing channels are complexed with Lgi1, the functionally unassigned product of the leucine-rich glioma inactivated gene 1 (LGI1), which is causative for an autosomal dominant form of lateral temporal lobe epilepsy (ADLTE) [8].
• In contrast, defective Lgi1 molecules identified in ADLTE patients fail to exert this effect resulting in channels with rapid inactivation kinetics [8].

Chemical compound and disease context of LGI1

• We also assessed risk by histologic subtype of breast cancer, by schedule of the progestin component of EPT, and by recency of use [9].
• Instead 5-HTP seems to be a universal tracer for EPT and foregut carcinoids [10].

Biological context of LGI1

• Loss of LGI1 expression, therefore, may be an important event in the progression of gliomas that leads to a more invasive phenotype in these cells [1].
• Here, using Affymetrix gene chip analysis, we show that reexpression of LGI1 in T98G cells results in the down-regulation of several MMP genes, in particular MMP1 and MMP3 [1].
• Furthermore, LGI1 expression promotes phosphorylation of AKT, which leads to phosphorylation of Raf1(Ser-259), an event shown previously to negatively regulate ERK1/2 signaling [1].
• Moreover, we provide evidence for genetic heterogeneity within this disorder, since several other families with a phenotype consistent with this type of epilepsy lack mutations in the LGI1 gene [11].
• Autosomal dominant lateral temporal lobe epilepsy previously has been linked to chromosome 10q22-q24, and recently mutations in the LGI1 gene (Leucine-rich gene, Glioma Inactivated) have been found in some autosomal dominant lateral temporal lobe epilepsy families [12].

Anatomical context of LGI1

• We have shown previously that the forced re-expression of LGI1 in different glioma cells inhibits proliferation, invasiveness, and anchorage-independent growth in cells null for its expression [1].
• Mutations in the leucine-rich, glioma-inactivated 1 gene, LGI1, cause autosomal-dominant lateral temporal lobe epilepsy via unknown mechanisms [13].
• We also propose that the evidence supporting the tumor suppressor role of LGI1 in malignant gliomas is weak and that further work is necessary to establish LGI1 role in glial cells [14].
• Finally, we show that normal secreted LGI1 specifically binds to the cell surface of differentiated PC12 cells [15].
• To our surprise, we observed that LGI1 expression after differentiation of murine neural stem cells was robust in neurons but negligible in glial cells, in agreement with immunohistochemistry studies on rodent brain [16].

Associations of LGI1 with chemical compounds

• We have now identified a missense mutation affecting a conserved cysteine residue in the extracellular region of the LGI1 protein [12].
• The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface [15].
• We investigated the influence on homocysteine levels of a 3-month treatment with a daily oral dose of 4 mg 17beta-estradiol (ET) or 4 mg ET combined with 10 mg dydrogesterone (EPT); the comparison group received placebo treatment [17].
• We conclude that the ET- and EPT-induced homocysteine changes in this study were not accompanied by a significant change in methionine-homocysteine flux rates and hypothesize that an estrogen-induced lowering of homocysteine levels is primarily part of a change in albumin metabolism [17].
• There was a significantly higher risk for continuous-combined than for sequential EPT use in Scandinavian studies where much higher total doses of progestin were used in continuous-combined than in sequential EPT [9].

Physical interactions of LGI1

• The mutated form of LGI1 fails to bind to ADAM22 [18].
• Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission [18].

Regulatory relationships of LGI1

• These data suggest that LGI1 plays a major role in suppressing the production of MMP1/3 through the phosphatidylinositol 3-kinase/ERK pathway [1].
• The negative family history, the ictal semiology, and the possibility that the spells were triggered by acoustic stimuli suggest IPEAF, and the search for the epitempin/LGI1 gene or other new gene mutations on a hair of the Maid of Orléans may enhance our knowledge about her presumed epilepsy [19].

Other interactions of LGI1

• LGI1 belongs to a subfamily of leucine-rich repeat genes comprising four members (LGI1-LGI4) in mammals [13].
• Genetic and expression analyses of all five zebrafish lgi genes revealed duplications of lgi1 and lgi2, each resulting in two paralogous gene copies with mostly nonoverlapping expression patterns [13].
• We show that ADAM22, a transmembrane protein that when mutated itself causes seizure, serves as a receptor for LGI1 [18].
• To test this hypothesis, we investigated LGI1 expression in parallel with expression of the neuronal marker NEF3 by real-time PCR on 30 malignant gliomas [16].
• Retroviral gene transfer into LGI1-deficient glioma-derived cell lines could not substantiate any difference to control infected cultures regarding growth rate, S phase transition, and maintenance of marker gene expression [20].

Analytical, diagnostic and therapeutic context of LGI1

• A redefinition of the C-terminal repeat and the application of sensitive sequence analysis methods enabled us to define a new superfamily of proteins carrying varying numbers of the novel EPTP repeats in combination with various extracellular domains [21].
• Fluorescence in situ hybridization (FISH) analysis showed LGI1 to be present on 10q24 in each of 11 glioma-derived cell lines evaluated [20].
• Immunohistochemistry demonstrated a strong expression of the LGI1 protein in normal brain tissue as well as in the majority of pilocytic astrocytomas and astrocytomas (WHO grade II) [22].
• AIM: A randomised controlled study to assess the effect of EPT on the outcome of patients suffering from acute cholangitis with gall bladder stones but with no CBD stones on initial endoscopic retrograde cholangiopancreatography [23].
• BACKGROUND: Biliary decompression with endoscopic sphincterotomy (EPT) is beneficial in patients with biliary obstruction due to common bile duct (CBD) stones [23].

References