LINGO3

Summary

LINGO3 (leucine rich repeat and Ig domain containing 3, HGNC:21206) is a protein-coding gene on chromosome 19p13.3, encoding Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 3 (P0C6S8).

Predicted to be located in membrane. Predicted to be active in extracellular matrix and extracellular space.

Source: NCBI Gene 645191 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 79 total
• MANE Select transcript: NM_001101391

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21206
Approved symbol	LINGO3
Name	leucine rich repeat and Ig domain containing 3
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	LERN2
Ensembl gene	ENSG00000220008
Ensembl biotype	protein_coding
OMIM	609792
Entrez	645191

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000585527, ENST00000698372, ENST00000935639

RefSeq mRNA: 1 — MANE Select: NM_001101391 NM_001101391

CCDS: CCDS45905

Canonical transcript exons

ENST00000698372 — 2 exons

Exon	Start	End
ENSE00002968835	2287164	2291822
ENSE00003973467	2308076	2308154

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 82.22.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1671 / max 29.9801, expressed in 53 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178157	0.1282	50
178158	0.0389	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	82.22	gold quality
putamen	UBERON:0001874	81.09	gold quality
caudate nucleus	UBERON:0001873	80.72	gold quality
monocyte	CL:0000576	78.97	gold quality
leukocyte	CL:0000738	78.67	gold quality
granulocyte	CL:0000094	77.75	gold quality
right hemisphere of cerebellum	UBERON:0014890	74.49	gold quality
blood	UBERON:0000178	73.83	gold quality
bone marrow cell	CL:0002092	72.24	silver quality
cerebellar cortex	UBERON:0002129	71.72	gold quality
cerebellar hemisphere	UBERON:0002245	71.63	gold quality
spleen	UBERON:0002106	71.09	gold quality
tendon of biceps brachii	UBERON:0008188	70.76	gold quality
cerebellum	UBERON:0002037	70.67	gold quality
upper leg skin	UBERON:0004262	68.75	silver quality
anterior cingulate cortex	UBERON:0009835	68.69	gold quality
amygdala	UBERON:0001876	68.26	gold quality
sural nerve	UBERON:0015488	68.07	gold quality
buccal mucosa cell	CL:0002336	67.67	gold quality
right frontal lobe	UBERON:0002810	66.74	gold quality
prefrontal cortex	UBERON:0000451	66.11	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	65.77	gold quality
hypothalamus	UBERON:0001898	65.25	gold quality
Brodmann (1909) area 9	UBERON:0013540	65.06	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	64.49	gold quality
brain	UBERON:0000955	63.77	gold quality
forebrain	UBERON:0001890	63.63	gold quality
spinal cord	UBERON:0002240	63.45	gold quality
small intestine Peyer’s patch	UBERON:0003454	63.33	gold quality
neocortex	UBERON:0001950	62.70	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.77

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting LINGO3, 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-3613-3P	100.00	76.36	7965
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-12114	98.70	63.45	730
HSA-MIR-10526-3P	97.86	64.97	1342
HSA-MIR-6802-5P	94.94	65.95	366

Literature-anchored findings (GeneRIF, showing 1)

• LINGO3 regulates mucosal tissue regeneration and promotes TFF2 dependent recovery from colitis. (PMID:33941035)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrtm2b	ENSDARG00000045811
danio_rerio	lingo3a	ENSDARG00000061970
danio_rerio		ENSDARG00000067815
danio_rerio	si:dkey-182i3.11	ENSDARG00000069270
danio_rerio	si:dkey-1j5.4	ENSDARG00000073747
danio_rerio	wu:fc23c09	ENSDARG00000088002
mus_musculus	Lingo3	ENSMUSG00000051067
rattus_norvegicus	Lingo3	ENSRNOG00000032569
drosophila_melanogaster	CG5819	FBGN0034717
drosophila_melanogaster	CG4781	FBGN0035043
caenorhabditis_elegans		WBGENE00006366

Paralogs (10): EPYC (ENSG00000083782), OGN (ENSG00000106809), ECM2 (ENSG00000106823), FMOD (ENSG00000122176), OMG (ENSG00000126861), OMD (ENSG00000127083), LUM (ENSG00000139329), KERA (ENSG00000139330), PRELP (ENSG00000188783), LINGO4 (ENSG00000213171)

Protein

Protein identifiers

Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 3 — P0C6S8 (reviewed: P0C6S8)

Alternative names: Leucine-rich repeat neuronal protein 2, Leucine-rich repeat neuronal protein 6B

All UniProt accessions (1): P0C6S8

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane.

RefSeq proteins (1): NP_001094861* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000372	LRRNT	Domain
IPR000483	Cys-rich_flank_reg_C	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050541	LRR_TM_domain-containing	Family

Pfam: PF00560, PF07679, PF13855

UniProt features (29 total): repeat 11, glycosylation site 8, domain 3, topological domain 2, signal peptide 1, chain 1, disulfide bond 1, sequence variant 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0C6S8-F1	86.16	0.72

Functional residue map

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

Disulfide bonds (1): 429–480

Glycosylation sites (8): 127, 185, 247, 257, 276, 324, 488, 512

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 24 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, BOYLAN_MULTIPLE_MYELOMA_C_D_UP, chr19p13, MEISSNER_NPC_HCP_WITH_H3_UNMETHYLATED, MIKKELSEN_MEF_HCP_WITH_H3K27ME3, ZNF22_TARGET_GENES, MIR1283, MIR548AV_3P, MIR8075, DESCARTES_FETAL_CEREBRUM_SKOR2_NPSR1_POSITIVE_CELLS, HARALAMBIEVA_PBMC_M_M_R_II_AGE_11_22YO_VACCINATED_VS_UNVACCINATED_7YR_DN, GOMF_MOLECULAR_TRANSDUCER_ACTIVITY, GSE8835_HEALTHY_VS_CLL_CD4_TCELL_DN, GSE1925_CTRL_VS_3H_IFNG_STIM_IFNG_PRIMED_MACROPHAGE_UP, GSE8921_UNSTIM_0H_VS_TLR1_2_STIM_MONOCYTE_3H_DN

GO Biological Process (0):

GO Molecular Function (2): signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
molecular transducer activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1180 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LINGO3	POU3F1	Q03052	433
LINGO3	EGFR	P00533	386
LINGO3	ANKS3	Q6ZW76	381
LINGO3	CENPP	Q6IPU0	374
LINGO3	TIAM2	Q8IVF5	374
LINGO3	DDX59	Q5T1V6	368
LINGO3	AGAP4	Q96P64	365
LINGO3	SKA2	Q8WVK7	359
LINGO3	DOT1L	Q8TEK3	354
LINGO3	FAM151B	Q6UXP7	352
LINGO3	F2RL3	Q96RI0	350
LINGO3	SCNN1G	P51170	349
LINGO3	ADAMTSL4	Q6UY14	332
LINGO3	GNG12	Q9UBI6	324
LINGO3	HCFC1R1	Q9NWW0	322

IntAct

0 interactions, top by confidence:

BioGRID (1): LINGO3 (Affinity Capture-RNA)

ESM2 similar proteins: A0A0B4J1F4, A0A0G2JXN2, A4FV98, A6QPA3, C9J798, C9JJ37, D3YWP0, D3ZVU9, D4A2K4, O43374, O70277, O75382, O95294, P0C6S8, P22674, P57775, Q08DS0, Q0GA42, Q3U410, Q3UGX3, Q4G0W2, Q4V892, Q5SUV1, Q5XIU1, Q6GQU6, Q6IA17, Q6PF15, Q6TDP3, Q6TDP4, Q7TNM2, Q7Z4K8, Q86WI3, Q8CIW5, Q8IZ69, Q8K430, Q8N531, Q8N8L6, Q8NE01, Q8WXI3, Q969K4

Diamond homologs: A0N0X6, A2AJ76, A2CG49, A4IGL7, A4IIW9, B3NS99, B4GBH0, B4HNW4, B4KPU0, B4MR28, B4P5Q9, B4QC63, G5EBF1, O75325, O95428, P0C6S8, P11627, P12960, P22063, P28685, P32004, P97924, Q02246, Q07409, Q09024, Q12860, Q290N5, Q32Q07, Q3UQ28, Q3URE9, Q3V1M1, Q5R482, Q61330, Q61809, Q62682, Q62845, Q63198, Q66HV9, Q69Z26, Q6AWJ9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	77
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

408 predictions. Top by Δscore:

Variant	Effect	Δscore
19:2301303:T:A	acceptor_gain	0.9100
19:2291773:TC:T	donor_gain	0.8900
19:2291775:ATG:A	donor_gain	0.8600
19:2294416:G:GT	donor_gain	0.8600
19:2291774:C:A	donor_gain	0.8400
19:2290023:C:CA	acceptor_gain	0.8300
19:2294416:G:T	donor_gain	0.8300
19:2301311:T:TA	acceptor_gain	0.8300
19:2287649:T:TA	acceptor_gain	0.8200
19:2288290:TG:T	donor_gain	0.8200
19:2291607:C:T	donor_gain	0.7600
19:2291938:G:C	donor_gain	0.7600
19:2303705:A:T	donor_gain	0.7200
19:2294417:A:T	donor_gain	0.7100
19:2303103:G:GT	donor_gain	0.7100
19:2291756:G:GT	donor_gain	0.7000
19:2301311:T:G	acceptor_gain	0.7000
19:2287653:T:A	acceptor_gain	0.6900
19:2291928:TGTAA:T	donor_gain	0.6900
19:2303179:C:CA	acceptor_gain	0.6900
19:2302822:G:GT	donor_gain	0.6800
19:2294993:C:CA	acceptor_gain	0.6700
19:2302753:C:G	donor_gain	0.6700
19:2287741:A:AG	donor_gain	0.6600
19:2291925:T:A	donor_gain	0.6500
19:2292038:A:G	donor_gain	0.6500
19:2301304:G:A	acceptor_gain	0.6500
19:2307807:G:T	donor_gain	0.6500
19:2290035:T:TA	acceptor_gain	0.6400
19:2307807:G:GT	donor_gain	0.6400

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000064570 (19:2289090 G>A,C), RS1000262098 (19:2289301 C>G,T), RS1000274202 (19:2288113 C>T), RS1000285383 (19:2293935 C>A,T), RS1000290914 (19:2293660 G>A,T), RS1000338618 (19:2293674 C>T), RS1000638704 (19:2306290 C>T), RS1000760563 (19:2309569 T>C), RS1000821056 (19:2301639 C>T), RS1000953219 (19:2298688 G>A), RS1001068444 (19:2288068 C>T), RS1001086611 (19:2302186 T>C), RS1001248066 (19:2302431 G>T), RS1001364311 (19:2302176 C>T), RS1001437437 (19:2306540 G>A)

Disease associations

OMIM: gene MIM:609792 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): myoepithelial tumor (MONDO:0002380)

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006218_107	Erosive tooth wear (severe vs non-severe)	4.000000e-06
GCST006226_8	Erosive tooth wear (severe vs none or mild)	5.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009208	Myoepithelioma	C04.557.435.585

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
hydroxyhydroquinone	decreases expression, decreases reaction	1
4-aminobenzhydrazide	decreases reaction, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases abundance, decreases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Metformin	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	increases expression	1
Tobacco Smoke Pollution	decreases methylation	1
Valproic Acid	increases methylation	1
Paclitaxel	affects cotreatment, increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT05266196	PHASE1/PHASE2	UNKNOWN	A Rollover Protocol to Allow for Continued Access to the LSD1 Inhibitor Seclidemstat (SP-2577)
NCT06239272	PHASE1/PHASE2	RECRUITING	NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
NCT06625190	PHASE1/PHASE2	RECRUITING	Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors
NCT06244420	Not specified	COMPLETED	Malignant Myoepithelioma of Bone and Soft Tissues: Diagnostic Imaging and Histology in Relation to Prognosis