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

2007-07-01   Nadia Gabellini 

University of Padua, Department of Biological Chemistry, Viale G. Colombo, 3; 35121, Padua, Italy.

Identity

HGNC
LOCATION
10q23.33
LOCUSID
ALIAS
ADLTE,ADPAEF,ADPEAF,EPITEMPIN,EPT,ETL1,IB1099

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).
Atlas Image
Organization of LGI1 gene, depicting isoform 1 exons (1-8);
exon size: (bp);
red: translated region;
blue: 5 UTR and 3UTR.

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.

Proteins

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.
Atlas Image
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 name
Malignant brain tumors.
Entity name
Epilepsy with auditory features (ADLTE).

Bibliography

Pubmed IDLast YearTitleAuthors
114044142001Repellent signaling by Slit requires the leucine-rich repeats.Battye R et al
129423232003Expression of the LGI1 gene product in astrocytic gliomas: downregulation with malignant progression.Besleaga R et al
146430042003No evidence for a seriously increased malignancy risk in LGI1-caused epilepsy.Brodtkorb E et al
98799931998A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors.Chernova OB et al
169905502006Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission.Fukata Y et al
165188562006Increased expression of LGI1 gene triggers growth inhibition and apoptosis of neuroblastoma cells.Gabellini N et al
120230202002The LGI1 gene involved in lateral temporal lobe epilepsy belongs to a new subfamily of leucine-rich repeat proteins.Gu W et al
175654252007Defining the expression pattern of the LGI1 gene in BAC transgenic mice.Head K et al
118101072002Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features.Kalachikov S et al
174715522007Leucine-rich repeat proteins of synapses.Ko J et al
78173991994The leucine-rich repeat: a versatile binding motif.Kobe B et al
119078062002Physical and functional characterization of the human LGI1 gene and its possible role in glioma development.Krex D et al
150477122004LGI1, 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 et al
116065932002Very large G protein-coupled receptor-1, the largest known cell surface protein, is highly expressed in the developing central nervous system.McMillan DR et al
119787702002Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy.Morante-Redolat JM et al
160002462005Differential expression of the LGI and SLIT families of genes in human cancer cells.Rossi MR et al
120959172002A common protein interaction domain links two recently identified epilepsy genes.Scheel H et al
165049452006The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1.Schulte U et al
158578552005ADPEAF mutations reduce levels of secreted LGI1, a putative tumor suppressor protein linked to epilepsy.Senechal KR et al
170679992006The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface.Sirerol-Piquer MS et al
109202292000Identification of the promoter, genomic structure, and mouse ortholog of LGI1.Somerville RP et al
122175142002The novel EPTP repeat defines a superfamily of proteins implicated in epileptic disorders.Staub E et al

Other Information

Locus ID:

NCBI: 9211
MIM: 604619
HGNC: 6572
Ensembl: ENSG00000108231

Variants:

dbSNP: 9211
ClinVar: 9211
TCGA: ENSG00000108231
COSMIC: LGI1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000108231ENST00000371413O95970
ENSG00000108231ENST00000371413A0A0S2Z4X3
ENSG00000108231ENST00000371418O95970
ENSG00000108231ENST00000371418A0A0S2Z4S7
ENSG00000108231ENST00000478763A0A0D9SFE3
ENSG00000108231ENST00000627420A0A0D9SFS5
ENSG00000108231ENST00000627699A0A0D9SFS5
ENSG00000108231ENST00000629035A0A0D9SFU4
ENSG00000108231ENST00000630047O95970
ENSG00000108231ENST00000630184A0A0D9SFH6
ENSG00000108231ENST00000630487A0A0D9SFS5
ENSG00000108231ENST00000635953A0A1B0GUD3
ENSG00000108231ENST00000636155A0A1B0GV33
ENSG00000108231ENST00000636232A0A0D9SFS5
ENSG00000108231ENST00000636754A0A0D9SFS5
ENSG00000108231ENST00000636946A0A0D9SFE3
ENSG00000108231ENST00000637037A0A1B0GWB4
ENSG00000108231ENST00000637611A0A0D9SFH6
ENSG00000108231ENST00000637689A0A1B0GVF6
ENSG00000108231ENST00000637925A0A1B0GTM5
ENSG00000108231ENST00000638049A0A1B0GVP2

Expression (GTEx)

0
5
10
15
20
25

Pathways

PathwaySourceExternal ID
Developmental BiologyREACTOMER-HSA-1266738
LGI-ADAM interactionsREACTOMER-HSA-5682910

References

Pubmed IDYearTitleCitations
205806152010Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series.220
118101072002Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features.125
242277252013Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors.84
119787702002Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy.73
163854512006A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.69
150790112004LGI1 mutations in autosomal dominant partial epilepsy with auditory features.41
191912272009LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy.38
234077602013Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping.38
197966862009LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology.33
122056522002LGI1 is mutated in familial temporal lobe epilepsy characterized by aphasic seizures.31

Citation

Nadia Gabellini

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

Atlas Genet Cytogenet Oncol Haematol. 2007-07-01

Online version: http://atlasgeneticsoncology.org/gene/311/lgi1-(leucine-rich-glioma-inactivated-protein-1-precursor)