LGI2

Summary

LGI2 (leucine rich repeat LGI family member 2, HGNC:18710) is a protein-coding gene on chromosome 4p15.2, encoding Leucine-rich repeat LGI family member 2 (Q8N0V4). Required for the development of soma-targeting inhibitory GABAergic synapses made by parvalbumin-positive basket cells.

Predicted to be involved in inhibitory synapse assembly. Predicted to be located in extracellular region.

Source: NCBI Gene 55203 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 16 total — 1 pathogenic
• MANE Select transcript: NM_018176

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18710
Approved symbol	LGI2
Name	leucine rich repeat LGI family member 2
Location	4p15.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1916, FLJ10675
Ensembl gene	ENSG00000153012
Ensembl biotype	protein_coding
OMIM	608301
Entrez	55203

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000382114, ENST00000512108, ENST00000950575

RefSeq mRNA: 1 — MANE Select: NM_018176 NM_018176

CCDS: CCDS3431

Canonical transcript exons

ENST00000382114 — 8 exons

Exon	Start	End
ENSE00001490957	24998847	25004268
ENSE00001643226	25017989	25018158
ENSE00001702355	25024820	25024891
ENSE00001716798	25028507	25028578
ENSE00001717063	25026868	25026939
ENSE00001746147	25030497	25030946
ENSE00001769200	25019167	25019238
ENSE00001784992	25012335	25012499

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 81.98.

FANTOM5 (CAGE): breadth broad, TPM avg 1.2363 / max 41.1401, expressed in 510 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51680	0.7128	405
51679	0.4515	241
51678	0.0719	41

Top tissues by expression

271 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
smooth muscle tissue	UBERON:0001135	81.98	gold quality
left uterine tube	UBERON:0001303	81.75	gold quality
mucosa of stomach	UBERON:0001199	79.78	gold quality
tibial nerve	UBERON:0001323	77.80	gold quality
right coronary artery	UBERON:0001625	77.68	gold quality
tendon of biceps brachii	UBERON:0008188	77.66	gold quality
left coronary artery	UBERON:0001626	77.08	gold quality
gall bladder	UBERON:0002110	76.80	gold quality
vermiform appendix	UBERON:0001154	76.76	gold quality
coronary artery	UBERON:0001621	76.57	gold quality
mucosa of urinary bladder	UBERON:0001259	76.38	gold quality
lower esophagus	UBERON:0013473	76.37	gold quality
lower esophagus muscularis layer	UBERON:0035833	76.36	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	75.88	gold quality
buccal mucosa cell	CL:0002336	75.50	gold quality
caecum	UBERON:0001153	75.50	gold quality
olfactory bulb	UBERON:0002264	75.14	silver quality
prefrontal cortex	UBERON:0000451	74.86	gold quality
body of uterus	UBERON:0009853	73.73	gold quality
parotid gland	UBERON:0001831	73.11	gold quality
nasal cavity epithelium	UBERON:0005384	72.77	gold quality
secondary oocyte	CL:0000655	72.37	silver quality
right hemisphere of cerebellum	UBERON:0014890	72.30	gold quality
cerebellar cortex	UBERON:0002129	72.24	gold quality
cerebellar hemisphere	UBERON:0002245	72.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	72.04	gold quality
myocardium	UBERON:0002349	72.04	gold quality
cerebellum	UBERON:0002037	71.94	gold quality
metanephros cortex	UBERON:0010533	71.59	gold quality
cingulate cortex	UBERON:0003027	71.51	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.65

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1

miRNA regulators (miRDB)

190 targeting LGI2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698

Literature-anchored findings (GeneRIF, showing 2)

• protein sequence analysis and patient-specific chromosomal deletions are provided for LGI2 as the prime candidate gene for partial epilepsy with pericentral spikes among the 52 genes known at locus 4p15 (PMID:20183877)
• The similarity of LGI2 share a common molecular disease mechanism causing genotypically distinct but phenotypically related forms of epilepsy. (PMID:20863412)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	lgi2b	ENSDARG00000069701
danio_rerio	lgi2a	ENSDARG00000111069
mus_musculus	Lgi2	ENSMUSG00000039252
rattus_norvegicus	Lgi2	ENSRNOG00000066201
drosophila_melanogaster	Con	FBGN0005775
drosophila_melanogaster	kek3	FBGN0028370
caenorhabditis_elegans	lron-9	WBGENE00011971
caenorhabditis_elegans		WBGENE00020649

Paralogs (22): CHADL (ENSG00000100399), LGI1 (ENSG00000108231), LGR6 (ENSG00000133067), CHAD (ENSG00000136457), LRIG3 (ENSG00000139263), LGR5 (ENSG00000139292), LRIG1 (ENSG00000144749), LRRTM2 (ENSG00000146006), LRIT1 (ENSG00000148602), LGI4 (ENSG00000153902), LRRC52 (ENSG00000162763), ELFN2 (ENSG00000166897), LGI3 (ENSG00000168481), LRG1 (ENSG00000171236), CPN2 (ENSG00000178772), LRIT3 (ENSG00000183423), LRRC26 (ENSG00000184709), LRIG2 (ENSG00000198799), LGR4 (ENSG00000205213), ELFN1 (ENSG00000225968), LRRC24 (ENSG00000254402), TRIL (ENSG00000255690)

Protein

Protein identifiers

Leucine-rich repeat LGI family member 2 — Q8N0V4 (reviewed: Q8N0V4)

Alternative names: LGI1-like protein 2, Leucine-rich glioma-inactivated protein 2

All UniProt accessions (2): Q8N0V4, H0YA65

UniProt curated annotations — full annotation on UniProt →

Function. Required for the development of soma-targeting inhibitory GABAergic synapses made by parvalbumin-positive basket cells.

Subcellular location. Secreted.

Tissue specificity. Brain, heart and placenta.

RefSeq proteins (1): NP_060646* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000483	Cys-rich_flank_reg_C	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR005492	EPTP	Repeat
IPR009039	EAR	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR051295	LGI_related	Family

Pfam: PF03736, PF13855

UniProt features (21 total): repeat 10, glycosylation site 4, sequence variant 2, domain 2, signal peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N0V4-F1	91.48	0.81

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (4): 70, 186, 271, 402

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5682910	LGI-ADAM interactions
R-HSA-1266738	Developmental Biology

MSigDB gene sets: 115 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_SYNAPSE_ASSEMBLY, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GGGTGGRR_PAX4_03, GOBP_CELL_JUNCTION_ORGANIZATION, KONDO_COLON_CANCER_HCP_WITH_H3K27ME1, GOBP_CELL_JUNCTION_ASSEMBLY, PIT1_Q6, MODULE_207, CUI_TCF21_TARGETS_2_UP, chr4p15, CHEN_METABOLIC_SYNDROM_NETWORK, MEISSNER_NPC_HCP_WITH_H3K4ME2, MIKKELSEN_MCV6_HCP_WITH_H3K27ME3

GO Biological Process (1): inhibitory synapse assembly (GO:1904862)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (1): extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
synapse assembly	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1008 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LGI2	ADAM23	O75077	730
LGI2	ADAM22	Q9P0K1	695
LGI2	ADAM28	Q9UKQ2	567
LGI2	ADAM11	O75078	563
LGI2	CCDC149	Q6ZUS6	484
LGI2	ARSG	Q96EG1	480
LGI2	SMOC1	Q9H4F8	464
LGI2	FBXL17	Q9UF56	443
LGI2	ANAPC4	Q9UJX5	437
LGI2	ZCCHC4	Q9H5U6	432
LGI2	NETO2	Q8NC67	427
LGI2	MPP3	Q13368	418
LGI2	HAUS3	Q68CZ6	413
LGI2	LGI4	Q8N135	411
LGI2	NXPH3	O95157	399

IntAct

4 interactions, top by confidence:

A	B	Type	Score
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
LGI2	PARN	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): ASS1 (Affinity Capture-MS), PARN (Affinity Capture-MS), LGI2 (Affinity Capture-MS), LGI2 (Affinity Capture-MS)

ESM2 similar proteins: A6QLU6, A8WCC4, B8JK39, J3S6Y1, O19011, O75051, P01137, P04202, P07200, P09533, P17246, P18341, P26013, P38570, P50414, P54831, P70206, P70207, Q0VBD0, Q13219, Q13797, Q1EGL1, Q25C36, Q2VWQ2, Q38HS2, Q4R4H3, Q5M900, Q5NDE9, Q5NDF0, Q5NDF1, Q5NDF2, Q5STE3, Q62919, Q6MZW2, Q6NRQ1, Q6QNK2, Q6YGZ1, Q80T32, Q8BW41, Q8CI19

Diamond homologs: O95970, P24014, Q1EGL0, Q1EGL1, Q1EGL2, Q4R4H3, Q5E9T6, Q5R945, Q6EMK4, Q8K1S1, Q8K406, Q8K4Y5, Q8K4Z0, Q8N0V4, Q8N135, Q8N145, Q9CZT5, Q9JIA1, Q9WVC1, P70193, O88279, Q80TR4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

16 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	12
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
441728	GRCh37/hg19 4p16.3-q35.2(chr4:68346-190957473)	Pathogenic

SpliceAI

1545 predictions. Top by Δscore:

Variant	Effect	Δscore
4:25011257:T:TA	donor_gain	1.0000
4:25012331:ACACC:A	donor_loss	1.0000
4:25012332:CACCT:C	donor_loss	1.0000
4:25012333:ACCTG:A	donor_loss	1.0000
4:25012334:C:CG	donor_loss	1.0000
4:25016248:T:TA	donor_gain	1.0000
4:25018157:CT:C	acceptor_gain	1.0000
4:25018159:C:CC	acceptor_gain	1.0000
4:25019239:C:CC	acceptor_gain	1.0000
4:25024988:T:TA	donor_gain	1.0000
4:25026861:AACTT:A	donor_loss	1.0000
4:25026862:ACTT:A	donor_loss	1.0000
4:25026863:CTT:C	donor_loss	1.0000
4:25026864:TTAC:T	donor_loss	1.0000
4:25026865:TACAG:T	donor_loss	1.0000
4:25026866:A:AC	donor_gain	1.0000
4:25026866:AC:A	donor_loss	1.0000
4:25026867:C:CT	donor_gain	1.0000
4:25026867:CA:C	donor_gain	1.0000
4:25026867:CAG:C	donor_gain	1.0000
4:25026867:CAGGT:C	donor_gain	1.0000
4:25030495:A:AC	donor_gain	1.0000
4:25030496:C:CC	donor_gain	1.0000
4:25003528:T:A	donor_gain	0.9900
4:25003739:A:AC	donor_gain	0.9900
4:25003740:C:CC	donor_gain	0.9900
4:25003741:TGTTC:T	donor_gain	0.9900
4:25011254:A:AC	donor_gain	0.9900
4:25011254:ACTT:A	donor_gain	0.9900
4:25011255:C:CC	donor_gain	0.9900

AlphaMissense

3627 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:25004059:C:G	D344H	1.000
4:25012378:C:A	W259C	1.000
4:25012378:C:G	W259C	1.000
4:25012380:A:G	W259R	1.000
4:25012380:A:T	W259R	1.000
4:25018064:A:G	C194R	1.000
4:25024820:A:G	L138P	1.000
4:25024888:G:C	F115L	1.000
4:25024888:G:T	F115L	1.000
4:25024889:A:C	F115C	1.000
4:25024890:A:G	F115L	1.000
4:25026868:A:G	L114P	1.000
4:25028507:A:G	L90P	1.000
4:25003560:G:C	P510R	0.999
4:25003560:G:T	P510H	0.999
4:25003641:T:A	D483V	0.999
4:25003642:C:G	D483H	0.999
4:25003643:A:C	S482R	0.999
4:25003643:A:T	S482R	0.999
4:25003645:T:G	S482R	0.999
4:25003648:C:A	G481W	0.999
4:25003656:A:G	L478P	0.999
4:25003866:A:G	F408S	0.999
4:25003902:G:C	P396R	0.999
4:25003902:G:T	P396H	0.999
4:25003916:G:C	S391R	0.999
4:25003916:G:T	S391R	0.999
4:25003917:C:A	S391I	0.999
4:25003918:T:G	S391R	0.999
4:25003929:A:G	L387P	0.999

dbSNP variants (sampled 300 via entrez): RS1000062768 (4:25020687 G>A), RS1000093391 (4:25020430 G>A), RS1000108086 (4:24992902 C>G), RS10001303 (4:25032553 T>A,C,G), RS1000153694 (4:25014254 G>A), RS1000186614 (4:25032340 A>G), RS1000220706 (4:25021950 C>A), RS1000224365 (4:25006165 G>A,T), RS1000276583 (4:25006358 G>A,C), RS1000293384 (4:25017926 T>A,C,G), RS1000317664 (4:24997108 T>C), RS1000329035 (4:24996847 A>C,T), RS10003820 (4:25007133 C>G,T), RS1000438255 (4:25026370 T>A), RS1000553366 (4:25030879 C>G,T)

Disease associations

OMIM: gene MIM:608301 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003995_19	Tonsillectomy	1.000000e-10
GCST005014_65	Tonsillectomy	1.000000e-10
GCST009391_1479	Metabolite levels	6.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007924	tonsillectomy risk measurement
EFO:0010414	triacylglycerol 52:2 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation	2
benzo(e)pyrene	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
2,6-dichloro-(1,4)benzoquinone	decreases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	decreases expression	1
Fulvestrant	decreases methylation	1
Doxorubicin	decreases expression	1
Folic Acid	increases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Methapyrilene	decreases methylation	1
Triclosan	decreases expression	1
Vanadates	decreases expression	1
Aflatoxin B1	decreases methylation, increases methylation	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.