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Gene Review

LGI1  -  leucine-rich, glioma inactivated 1

Homo sapiens

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Disease relevance of LGI1


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


Biological context of LGI1


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


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


  1. LGI1, a putative tumor metastasis suppressor gene, controls in vitro invasiveness and expression of matrix metalloproteinases in glioma cells through the ERK1/2 pathway. Kunapuli, P., Kasyapa, C.S., Hawthorn, L., Cowell, J.K. J. Biol. Chem. (2004) [Pubmed]
  2. LGI1 mutations in temporal lobe epilepsies. Berkovic, S.F., Izzillo, P., McMahon, J.M., Harkin, L.A., McIntosh, A.M., Phillips, H.A., Briellmann, R.S., Wallace, R.H., Mazarib, A., Neufeld, M.Y., Korczyn, A.D., Scheffer, I.E., Mulley, J.C. Neurology (2004) [Pubmed]
  3. ADPEAF mutations reduce levels of secreted LGI1, a putative tumor suppressor protein linked to epilepsy. Senechal, K.R., Thaller, C., Noebels, J.L. Hum. Mol. Genet. (2005) [Pubmed]
  4. A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors. Chernova, O.B., Somerville, R.P., Cowell, J.K. Oncogene (1998) [Pubmed]
  5. Two novel epilepsy-linked mutations leading to a loss of function of LGI1. Chabrol, E., Popescu, C., Gourfinkel-An, I., Trouillard, O., Depienne, C., Senechal, K., Baulac, M., LeGuern, E., Baulac, S. Arch. Neurol. (2007) [Pubmed]
  6. The effect of expressive physical touch on patients with dementia. Kim, E.J., Buschmann, M.T. International journal of nursing studies. (1999) [Pubmed]
  7. Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Kalachikov, S., Evgrafov, O., Ross, B., Winawer, M., Barker-Cummings, C., Martinelli Boneschi, F., Choi, C., Morozov, P., Das, K., Teplitskaya, E., Yu, A., Cayanis, E., Penchaszadeh, G., Kottmann, A.H., Pedley, T.A., Hauser, W.A., Ottman, R., Gilliam, T.C. Nat. Genet. (2002) [Pubmed]
  8. The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1. Schulte, U., Thumfart, J.O., Klöcker, N., Sailer, C.A., Bildl, W., Biniossek, M., Dehn, D., Deller, T., Eble, S., Abbass, K., Wangler, T., Knaus, H.G., Fakler, B. Neuron (2006) [Pubmed]
  9. An overview of menopausal oestrogen-progestin hormone therapy and breast cancer risk. Lee, S.A., Ross, R.K., Pike, M.C. Br. J. Cancer (2005) [Pubmed]
  10. The role of PET in localization of neuroendocrine and adrenocortical tumors. Eriksson, B., Bergström, M., Sundin, A., Juhlin, C., Orlefors, H., Oberg, K., Långström, B. Ann. N. Y. Acad. Sci. (2002) [Pubmed]
  11. Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Morante-Redolat, J.M., Gorostidi-Pagola, A., Piquer-Sirerol, S., Sáenz, A., Poza, J.J., Galán, J., Gesk, S., Sarafidou, T., Mautner, V.F., Binelli, S., Staub, E., Hinzmann, B., French, L., Prud'homme, J.F., Passarelli, D., Scannapieco, P., Tassinari, C.A., Avanzini, G., Martí-Massó, J.F., Kluwe, L., Deloukas, P., Moschonas, N.K., Michelucci, R., Siebert, R., Nobile, C., Pérez-Tur, J., López de Munain, A. Hum. Mol. Genet. (2002) [Pubmed]
  12. LGI1 is mutated in familial temporal lobe epilepsy characterized by aphasic seizures. Gu, W., Brodtkorb, E., Steinlein, O.K. Ann. Neurol. (2002) [Pubmed]
  13. Using gene-history and expression analyses to assess the involvement of LGI genes in human disorders. Gu, W., Gibert, Y., Wirth, T., Elischer, A., Bloch, W., Meyer, A., Steinlein, O.K., Begemann, G. Mol. Biol. Evol. (2005) [Pubmed]
  14. LGI1: a gene involved in epileptogenesis and glioma progression? Gu, W., Brodtkorb, E., Piepoli, T., Finocchiaro, G., Steinlein, O.K. Neurogenetics (2005) [Pubmed]
  15. The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface. Sirerol-Piquer, M.S., Ayerdi-Izquierdo, A., Morante-Redolat, J.M., Herranz-P??rez, V., Favell, K., Barker, P.A., P??rez-Tur, J. Hum. Mol. Genet. (2006) [Pubmed]
  16. Expression studies in gliomas and glial cells do not support a tumor suppressor role for LGI1. Piepoli, T., Jakupoglu, C., Gu, W., Lualdi, E., Suarez-Merino, B., Poliani, P.L., Cattaneo, M.G., Ortino, B., Goplen, D., Wang, J., Mola, R., Inverardi, F., Frassoni, C., Bjerkvig, R., Steinlein, O., Vicentini, L.M., Brüstle, O., Finocchiaro, G. Neuro-oncology (2006) [Pubmed]
  17. Oral estradiol decreases plasma homocysteine, vitamin B6, and albumin in postmenopausal women but does not change the whole-body homocysteine remethylation and transmethylation flux. Smolders, R.G., de Meer, K., Kenemans, P., Jakobs, C., Kulik, W., van der Mooren, M.J. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  18. Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission. Fukata, Y., Adesnik, H., Iwanaga, T., Bredt, D.S., Nicoll, R.A., Fukata, M. Science (2006) [Pubmed]
  19. "I heard voices...": from semiology, a historical review, and a new hypothesis on the presumed epilepsy of Joan of Arc. d'Orsi, G., Tinuper, P. Epilepsy & behavior : E&B. (2006) [Pubmed]
  20. Physical and functional characterization of the human LGI1 gene and its possible role in glioma development. Krex, D., Hauses, M., Appelt, H., Mohr, B., Ehninger, G., Schackert, H.K., Schackert, G. Acta Neuropathol. (2002) [Pubmed]
  21. The novel EPTP repeat defines a superfamily of proteins implicated in epileptic disorders. Staub, E., Pérez-Tur, J., Siebert, R., Nobile, C., Moschonas, N.K., Deloukas, P., Hinzmann, B. Trends Biochem. Sci. (2002) [Pubmed]
  22. Expression of the LGI1 gene product in astrocytic gliomas: downregulation with malignant progression. Besleaga, R., Montesinos-Rongen, M., Perez-Tur, J., Siebert, R., Deckert, M. Virchows Arch. (2003) [Pubmed]
  23. A randomised controlled trial of endoscopic sphincterotomy in acute cholangitis without common bile duct stones. Hui, C.K., Lai, K.C., Wong, W.M., Yuen, M.F., Lam, S.K., Lai, C.L. Gut (2002) [Pubmed]
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