Atlas of Genetics and Cytogenetics in Oncology and Haematology
LGI1 (Leucine-rich, Glioma Inactivated protein 1 precursor)
| Identity |
| Other names | ADPEAF |
| EPT | |
| Epitempin-1 | |
| ETL1 | |
| IB1099 | |
| uc001kjc.1 | |
| HGNC | LGI1 |
| Location | 10q23.33 |
| Location_base_pair | Starts at 95507556 and ends at 95547906 bp from pter ( according to hg18-Mar_2006). |
| Local_order | Plus strand orientation, between C10orf4 (protein isoform FRA10AC1-2) and TMEM20 (Transmembrane protein 20). |
| DNA/RNA |
| Note | LGI1 gene spans a 40,274 bp region of chromosome 10 (95,507,632 - 95,547,906) NCBI assembly annotation: NC_000010.9; NT_030059.12. Alternate Celera assembly: AC_000053.1; NW_924884.1. LGI1 is considered a metastasis suppressor gene; it is also implicated in Autosomal Dominant Lateral Temporal Lobe Epilepsy (ADLTE). |
 | |
| Organization of LGI1 gene, depicting isoform 1 exons (1-8); exon size: (bp); red: translated region; blue: 5' UTR and 3'UTR. | |
| Description | The LGI1 gene was isolated by positional cloning from a glioblastoma cell line (T98G) bearing a balanced translocation t(10;19)(q24;q13). LGI1 gene comprises 8 exons. Exon 1 contains the 5 UTR (224 bp) and encodes the start methione. The size of exon 8 and the position of the stop codon are different in isoform 1 and 2. The 3UTR consists of 356 bp in isoform 1 and of 386 bp in isoform 2. A minimal promoter region is located immediately upstream of the TSS. Two Poly (A) sites are predicted by SVM from UCSC Genome Browser at the following positions: chr10:95547796-95547828 and chr10:95547881-95547919. STS markers: IB1099; EST307318; RH51322; SHGC-155057. |
| Transcription | Isoform 1 mRNA is composed of 2290 bases. Alternative splicing produces isoform 2 consisting of 1456 bases with a shorter exon 8 (425 bases): |
| Pseudogene | None. |
| Protein |
| Note | The unprocessed precursor of LGI1 comprises 557 Amino Acids with a Molecular weight of 63818 Da (isoform 1, UniProtKB/Swiss-Prot ID: 095970). Three potential N-linked glycosilation sites have been identified at AA positions: 192, 277 and 422. Isoform 2 includes a sequence variation (AA: 280-291) and lacks the C-terminal AA stretch (292-557) yielding a protein length of 291 AA (Isoform ID: O95970-2). Isoform 1 is potentially secreted. |
 | |
| Predicted domains of LGI1 protein (isoform 1): - signal peptide (SP, AA: 1-34); - N-terminal LRRNT (AA: 41-71); - LRRs domains 1-3 (AA: 90-113, 114-137 and 138-161); - C-terminal LRRCT (AA: 173-222). The C-terminal half includes the EAR/EPTP repeats 1-7 (AA: 224-267, 270-313, 316-364, 365-415, 418-462, 463-506, and 509-552). | |
| Description | The N-terminal sequence of LGI1 precursor consists of a cleavable N-terminal signal peptide and of three leucine-rich repeats (LRRs) flanked by N-terminal and C-terminal cysteine-rich domains (LRRNT and LRRCT). The LRR domains are structurally similar to arcs and are generally involved in protein-protein interaction. The C-terminal portion of LGI1 contains 7 repeats, termed Epilepsy Associated Repeats (EAR) or Epitempin (EPTP). The repeats potentially fold as beta-sheet and form a seven-bladed beta-propeller structure. Similar domains, identified in a number of proteins, probably represent protein interfaces. Isoform 2 lacks the six C-terminal EAR/EPTP domains. |
| Expression | LGI1 is highly expressed in neural tissue, particularly in specific brain regions comprising both neurons and glial cells; strong expression is also reported in some areas of the prostate, kidney, sebaceous glands, islets of Langerhans, endometrium, ovary and testis. Expression is low or absent in the majority of glioma, glioblastoma, neuroblastoma, melanoma and breast cancer cell lines. The decrease of LGI1 expression correlates with the increasing grade of malignancy in astrocytic gliomas. DNA microarray data substantiate high expression in brain, spinal cord, DRG, and in pituitary gland. The expression profiles by SAGE and EST number support high expression in cerebellum and cerebrum, peripheral nerve, and also in B-lymphocytes, eye, lung, muscle, testis, and thymus; low or absent expression in neoplasia and tumors. |
| Localisation | Isoform 1 can be secreted, whereas a shorter isoform (which might correspond to isoform 2) is retained within the cell. Some mutants of LGI1 (isoform 1) linked to ADLTE, fail to be secreted and remain in the endoplasmic reticulum and Golgi. |
| Function | LGI1 is involved in the control of cell proliferation, cell migration and neurogenesis. Like other neuronal LRR proteins LGI1 may modulate synaptic function. Re-expression in LGI1-null glioblastoma cells decreases cell proliferation through the inhibition of the ERK1/2 pathway and consequent down-regulation of matrix metalloproteinases. Increased expression in neuroblastoma cells reduces proliferation and triggers intrinsic apoptosis by inhibiting the PI3K/AKT pathway. LGI1 forms membrane complexes with Kv1.1 potassium channels within the cell antagonizing the N-type inactivation by the Kvbeta1 subunit. It has been recognized as a ligand of the trans-membrane protein receptor ADAM22, which also causes seizure when mutated. |
| Homology | It belongs to a family comprising four highly homologous members denoted LGI1, LGI2, LGI3, and LGI4. LRR repeats flanked by cysteine rich regions, are also part of adhesive proteins and receptors of the LRR superfamily. With respect to this domain LGI1 is particularly related to the Drosophila protein slit, involved in growth-cone guidance and neuronal migration; and to the portion of the mammalian Trk receptors involved in neurotrophin binding. These proteins are crucial for the development of the nervous system. A comparable role for LGI1 is consistent with its involvement in epilepsy and tumors. The C-terminal seven-fold repeat shows the largest identity with the other members of the LGI protein family, and with a segment of the G protein coupled receptor MASS1/VLGR1, which carries mutations in a mouse model of audiogenic epilepsy. |
| Mutations |
| Note | The human LGI1 gene disclosed about 200 Single Nucleotide Polimorphism (SNP), NCBI Assembly Reference Cluster Report: rs1111820 - rs3083468. Heterozygous point mutations are associated with ADLTE. Large-scale homozygous mutations are linked to the development of brain malignancy. Apparently the incidence of brain tumors is not increased in ADLTE. |
| Germinal | Several loss of function mutations (missense/nonsense, splicing, small deletions and insertions) have been reported in ADLTE patients. |
| Somatic | Complete loss of LGI1 expression is associated with malignant brain tumors. Rearrangement or deletion of the region 10q23-q26, following the complete loss of one copy of chromosome 10, frequently occurs in high-grade gliomas. Genetic abnormalities in this region, comprising tumor suppressor genes such as PTEN and DMBT next to the metastasis suppressor LGI1 gene, enhance the malignant progression. Even if rearrangements or mutations of LGI1 locus are absent in low-grade tumors LGI1 expression is often reduced, possibly due to epigenetic silencing. |
| Implicated in |
| Entity | Malignant brain tumors. |
| Entity | Epilepsy with auditory features (ADLTE). |
| To be noted |
| Consultation of The Cancer Genome Anatomy Project (CGAP) for breakpoints of region 10q24 associated with cancer yielded several balanced and unbalanced abnormalities, raising the possibility that interruption of LGI1 gene may be implicated in additional cancer pathologies. |
| External links |
| Bibliography |
| The leucine-rich repeat: a versatile binding motif. |
| Kobe B, Deisenhofer J |
| Trends in biochemical sciences. 1994 ; 19 (10) : 415-421. |
| PMID 7817399 |
| A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors. |
| Chernova OB, Somerville RP, Cowell JK |
| Oncogene. 1998 ; 17 (22) : 2873-2881. |
| PMID 9879993 |
| Identification of the promoter, genomic structure, and mouse ortholog of LGI1. |
| Somerville RP, Chernova O, Liu S, Shoshan Y, Cowell JK |
| Mammalian genome : official journal of the International Mammalian Genome Society. 2000 ; 11 (8) : 622-627. |
| PMID 10920229 |
| Repellent signaling by Slit requires the leucine-rich repeats. |
| Battye R, Stevens A, Perry RL, Jacobs JR |
| The Journal of neuroscience : the official journal of the Society for Neuroscience. 2001 ; 21 (12) : 4290-4298. |
| PMID 11404414 |
| The LGI1 gene involved in lateral temporal lobe epilepsy belongs to a new subfamily of leucine-rich repeat proteins. |
| Gu W, Wevers A, Schrder H, Grzeschik KH, Derst C, Brodtkorb E, de Vos R, Steinlein OK |
| FEBS letters. 2002 ; 519 (1-3) : 71-76. |
| PMID 12023020 |
| 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 AH, Pedley TA, Hauser WA, Ottman R, Gilliam TC |
| Nature genetics. 2002 ; 30 (3) : 335-341. |
| PMID 11810107 |
| 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 HK, Schackert G |
| Acta neuropathologica. 2002 ; 103 (3) : 255-266. |
| PMID 11907806 |
| Very large G protein-coupled receptor-1, the largest known cell surface protein, is highly expressed in the developing central nervous system. |
| McMillan DR, Kayes-Wandover KM, Richardson JA, White PC |
| The Journal of biological chemistry. 2002 ; 277 (1) : 785-792. |
| PMID 11606593 |
| Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. |
| Morante-Redolat JM, Gorostidi-Pagola A, Piquer-Sirerol S, Senz A, Poza JJ, Galn J, Gesk S, Sarafidou T, Mautner VF, Binelli S, Staub E, Hinzmann B, French L, Prud'homme JF, Passarelli D, Scannapieco P, Tassinari CA, Avanzini G, Mart-Mass JF, Kluwe L, Deloukas P, Moschonas NK, Michelucci R, Siebert R, Nobile C, Prez-Tur J, Lpez de Munain A |
| Human molecular genetics. 2002 ; 11 (9) : 1119-1128. |
| PMID 11978770 |
| A common protein interaction domain links two recently identified epilepsy genes. |
| Scheel H, Tomiuk S, Hofmann K |
| Human molecular genetics. 2002 ; 11 (15) : 1757-1762. |
| PMID 12095917 |
| The novel EPTP repeat defines a superfamily of proteins implicated in epileptic disorders. |
| Staub E, Prez-Tur J, Siebert R, Nobile C, Moschonas NK, Deloukas P, Hinzmann B |
| Trends in biochemical sciences. 2002 ; 27 (9) : 441-444. |
| PMID 12217514 |
| 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 Archiv : an international journal of pathology. 2003 ; 443 (4) : 561-564. |
| PMID 12942323 |
| No evidence for a seriously increased malignancy risk in LGI1-caused epilepsy. |
| Brodtkorb E, Nakken KO, Steinlein OK |
| Epilepsy research. 2003 ; 56 (2-3) : 205-208. |
| PMID 14643004 |
| Suppression of the cell proliferation and invasion phenotypes in glioma cells by the LGI1 gene. |
| Kunapuli P, Chitta KS, Cowell JK |
| Oncogene. 2003 ; 22 (26) : 3985-3991. |
| PMID 12821932 |
| 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 CS, Hawthorn L, Cowell JK |
| The Journal of biological chemistry. 2004 ; 279 (22) : 23151-23157. |
| PMID 15047712 |
| Differential expression of the LGI and SLIT families of genes in human cancer cells. |
| Rossi MR, Huntoon K, Cowell JK |
| Gene. 2005 ; 356 : 85-90. |
| PMID 16000246 |
| ADPEAF mutations reduce levels of secreted LGI1, a putative tumor suppressor protein linked to epilepsy. |
| Senechal KR, Thaller C, Noebels JL |
| Human molecular genetics. 2005 ; 14 (12) : 1613-1620. |
| PMID 15857855 |
| Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission. |
| Fukata Y, Adesnik H, Iwanaga T, Bredt DS, Nicoll RA, Fukata M |
| Science (New York, N.Y.). 2006 ; 313 (5794) : 1792-1795. |
| PMID 16990550 |
| Increased expression of LGI1 gene triggers growth inhibition and apoptosis of neuroblastoma cells. |
| Gabellini N, Masola V, Quartesan S, Oselladore B, Nobile C, Michelucci R, Curtarello M, Parolin C, Pal G |
| Journal of cellular physiology. 2006 ; 207 (3) : 711-721. |
| PMID 16518856 |
| The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1. |
| Schulte U, Thumfart JO, Klcker N, Sailer CA, Bildl W, Biniossek M, Dehn D, Deller T, Eble S, Abbass K, Wangler T, Knaus HG, Fakler B |
| Neuron. 2006 ; 49 (5) : 697-706. |
| PMID 16504945 |
| The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface. |
| Sirerol-Piquer MS, Ayerdi-Izquierdo A, Morante-Redolat JM, Herranz-Prez V, Favell K, Barker PA, Prez-Tur J |
| Human molecular genetics. 2006 ; 15 (23) : 3436-3445. |
| PMID 17067999 |
| Defining the expression pattern of the LGI1 gene in BAC transgenic mice. |
| Head K, Gong S, Joseph S, Wang C, Burkhardt T, Rossi MR, LaDuca J, Matsui S, Vaughan M, Hicks DG, Heintz N, Cowell JK |
| Mammalian genome : official journal of the International Mammalian Genome Society. 2007 ; 18 (5) : 328-337. |
| PMID 17565425 |
| Leucine-rich repeat proteins of synapses. |
| Ko J, Kim E |
| Journal of neuroscience research. 2007 ; 85 (13) : 2824-2832. |
| PMID 17471552 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 07-2007 | Nadia Gabellini |
| University of Padua, Department of Biological Chemistry, Viale G. Colombo, 3; 35121, Padua, Italy. |
| Citation |
| This paper should be referenced as such : |
| Gabellini N . LGI1 (Leucine-rich, Glioma Inactivated protein 1 precursor). Atlas Genet Cytogenet Oncol Haematol. July 2007 . URL : http://AtlasGeneticsOncology.org/Genes/LGI1ID311ch10q23.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Sun Nov 9 19:42:54 2008 |
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