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LGI1 (Leucine-rich, Glioma Inactivated protein 1 precursor)

Written2007-07Nadia Gabellini
University of Padua, Department of Biological Chemistry, Viale G. Colombo, 3; 35121, Padua, Italy.

(Note : for Links provided by Atlas : click)

Identity

Alias_namesEPT
epilepsy
Alias_symbol (synonym)IB1099
ETL1
EPITEMPIN
Other aliasADPEAF
Epitempin-1
uc001kjc.1
HGNC (Hugo) LGI1
LocusID (NCBI) 9211
Atlas_Id 311
Location 10q23.33  [Link to chromosome band 10q23]
Location_base_pair Starts at 95517566 and ends at 95557931 bp from pter ( according to hg19-Feb_2009)  [Mapping LGI1.png]
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 3'UTR 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

Note
  
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.

Bibliography

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
 
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
 
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
 
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, Palù G
Journal of cellular physiology. 2006 ; 207 (3) : 711-721.
PMID 16518856
 
The LGI1 gene involved in lateral temporal lobe epilepsy belongs to a new subfamily of leucine-rich repeat proteins.
Gu W, Wevers A, Schröder H, Grzeschik KH, Derst C, Brodtkorb E, de Vos R, Steinlein OK
FEBS letters. 2002 ; 519 (1-3) : 71-76.
PMID 12023020
 
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
 
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
 
Leucine-rich repeat proteins of synapses.
Ko J, Kim E
Journal of neuroscience research. 2007 ; 85 (13) : 2824-2832.
PMID 17471552
 
The leucine-rich repeat: a versatile binding motif.
Kobe B, Deisenhofer J
Trends in biochemical sciences. 1994 ; 19 (10) : 415-421.
PMID 7817399
 
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
 
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
 
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, S´enz A, Poza JJ, Gal´n 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, Martí-Massó JF, Kluwe L, Deloukas P, Moschonas NK, Michelucci R, Siebert R, Nobile C, Pérez-Tur J, López de Munain A
Human molecular genetics. 2002 ; 11 (9) : 1119-1128.
PMID 11978770
 
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
 
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 epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1.
Schulte U, Thumfart JO, Klöcker 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
 
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
 
The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface.
Sirerol-Piquer MS, Ayerdi-Izquierdo A, Morante-Redolat JM, Herranz-Pérez V, Favell K, Barker PA, Pérez-Tur J
Human molecular genetics. 2006 ; 15 (23) : 3436-3445.
PMID 17067999
 
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
 
The novel EPTP repeat defines a superfamily of proteins implicated in epileptic disorders.
Staub E, Pérez-Tur J, Siebert R, Nobile C, Moschonas NK, Deloukas P, Hinzmann B
Trends in biochemical sciences. 2002 ; 27 (9) : 441-444.
PMID 12217514
 

Citation

This paper should be referenced as such :
Gabellini, N
LGI1 (leucine-rich, glioma inactivated protein 1 precursor)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(1):50-52.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/LGI1ID311ch10q23.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Nervous system: Astrocytic tumors


External links

Nomenclature
HGNC (Hugo)LGI1   6572
Cards
AtlasLGI1ID311ch10q23
Entrez_Gene (NCBI)LGI1  9211  leucine-rich, glioma inactivated 1
AliasesADLTE; ADPAEF; ADPEAF; EPITEMPIN; 
EPT; ETL1; IB1099
GeneCards (Weizmann)LGI1
Ensembl hg19 (Hinxton)ENSG00000108231 [Gene_View]  chr10:95517566-95557931 [Contig_View]  LGI1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000108231 [Gene_View]  chr10:95517566-95557931 [Contig_View]  LGI1 [Vega]
ICGC DataPortalENSG00000108231
TCGA cBioPortalLGI1
AceView (NCBI)LGI1
Genatlas (Paris)LGI1
WikiGenes9211
SOURCE (Princeton)LGI1
Genetics Home Reference (NIH)LGI1
Genomic and cartography
GoldenPath hg19 (UCSC)LGI1  -     chr10:95517566-95557931 +  10q24   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)LGI1  -     10q24   [Description]    (hg38-Dec_2013)
EnsemblLGI1 - 10q24 [CytoView hg19]  LGI1 - 10q24 [CytoView hg38]
Mapping of homologs : NCBILGI1 [Mapview hg19]  LGI1 [Mapview hg38]
OMIM600512   604619   
Gene and transcription
Genbank (Entrez)AB209408 AF055636 AF473548 AK289706 AK303956
RefSeq transcript (Entrez)NM_001308275 NM_001308276 NM_005097
RefSeq genomic (Entrez)NC_000010 NC_018921 NG_011832 NT_030059 NW_004929376
Consensus coding sequences : CCDS (NCBI)LGI1
Cluster EST : UnigeneHs.533670 [ NCBI ]
CGAP (NCI)Hs.533670
Alternative Splicing GalleryENSG00000108231
Gene ExpressionLGI1 [ NCBI-GEO ]   LGI1 [ EBI - ARRAY_EXPRESS ]   LGI1 [ SEEK ]   LGI1 [ MEM ]
Gene Expression Viewer (FireBrowse)LGI1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9211
GTEX Portal (Tissue expression)LGI1
Protein : pattern, domain, 3D structure
UniProt/SwissProtO95970   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO95970  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO95970
Splice isoforms : SwissVarO95970
PhosPhoSitePlusO95970
Domaine pattern : Prosite (Expaxy)EAR (PS50912)   
Domains : Interpro (EBI)Cys-rich_flank_reg_C    EAR    EPTP    L_dom-like    Leu-rich_rpt    Leu-rich_rpt_typical-subtyp    LRRNT   
Domain families : Pfam (Sanger)EPTP (PF03736)    LRR_8 (PF13855)   
Domain families : Pfam (NCBI)pfam03736    pfam13855   
Domain families : Smart (EMBL)LRR_TYP (SM00369)  LRRCT (SM00082)  LRRNT (SM00013)  
Conserved Domain (NCBI)LGI1
DMDM Disease mutations9211
Blocks (Seattle)LGI1
SuperfamilyO95970
Human Protein AtlasENSG00000108231
Peptide AtlasO95970
HPRD05216
IPIIPI00021091   IPI00334395   IPI00945485   
Protein Interaction databases
DIP (DOE-UCLA)O95970
IntAct (EBI)O95970
FunCoupENSG00000108231
BioGRIDLGI1
STRING (EMBL)LGI1
ZODIACLGI1
Ontologies - Pathways
QuickGOO95970
Ontology : AmiGOreceptor binding  receptor binding  protein binding  extracellular region  extracellular space  extracellular space  nervous system development  axon guidance  cell proliferation  cell junction  positive regulation of cell growth  neuron projection development  synapse  positive regulation of synaptic transmission  protein homooligomerization  
Ontology : EGO-EBIreceptor binding  receptor binding  protein binding  extracellular region  extracellular space  extracellular space  nervous system development  axon guidance  cell proliferation  cell junction  positive regulation of cell growth  neuron projection development  synapse  positive regulation of synaptic transmission  protein homooligomerization  
REACTOMEO95970 [protein]
REACTOME Pathways5682910 [pathway]   
NDEx NetworkLGI1
Atlas of Cancer Signalling NetworkLGI1
Wikipedia pathwaysLGI1
Orthology - Evolution
OrthoDB9211
GeneTree (enSembl)ENSG00000108231
Phylogenetic Trees/Animal Genes : TreeFamLGI1
HOVERGENO95970
HOGENOMO95970
Homologs : HomoloGeneLGI1
Homology/Alignments : Family Browser (UCSC)LGI1
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerLGI1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)LGI1
dbVarLGI1
ClinVarLGI1
1000_GenomesLGI1 
Exome Variant ServerLGI1
ExAC (Exome Aggregation Consortium)LGI1 (select the gene name)
Genetic variants : HAPMAP9211
Genomic Variants (DGV)LGI1 [DGVbeta]
DECIPHER (Syndromes)10:95517566-95557931  ENSG00000108231
CONAN: Copy Number AnalysisLGI1 
Mutations
ICGC Data PortalLGI1 
TCGA Data PortalLGI1 
Broad Tumor PortalLGI1
OASIS PortalLGI1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICLGI1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDLGI1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch LGI1
DgiDB (Drug Gene Interaction Database)LGI1
DoCM (Curated mutations)LGI1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)LGI1 (select a term)
intoGenLGI1
NCG5 (London)LGI1
Cancer3DLGI1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM600512    604619   
Orphanet14757   
MedgenLGI1
Genetic Testing Registry LGI1
NextProtO95970 [Medical]
TSGene9211
GENETestsLGI1
Huge Navigator LGI1 [HugePedia]
snp3D : Map Gene to Disease9211
BioCentury BCIQLGI1
ClinGenLGI1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD9211
Chemical/Pharm GKB GenePA30349
Clinical trialLGI1
Miscellaneous
canSAR (ICR)LGI1 (select the gene name)
Other databasewww.gensat.org
Probes
Litterature
PubMed61 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineLGI1
EVEXLGI1
GoPubMedLGI1
iHOPLGI1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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