LINGO1

Summary

LINGO1 (leucine rich repeat and Ig domain containing 1, HGNC:21205) is a protein-coding gene on chromosome 15q24.3, encoding Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (Q96FE5). Functional component of the Nogo receptor signaling complex (RTN4R/NGFR) in RhoA activation responsible for some inhibition of axonal regeneration by myelin-associated factors.

Predicted to enable epidermal growth factor receptor binding activity. Predicted to act upstream of or within negative regulation of oligodendrocyte differentiation; negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; and neuron development. Predicted to be located in plasma membrane. Predicted to be active in several cellular components, including extracellular space; glutamatergic synapse; and presynapse. Implicated in autosomal recessive intellectual developmental disorder 64 and glaucoma.

Source: NCBI Gene 84894 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, autosomal recessive 64 (Moderate, GenCC)
• GWAS associations: 17
• Clinical variants (ClinVar): 135 total — 2 pathogenic
• Phenotypes (HPO): 14
• Druggable target: yes
• MANE Select transcript: NM_032808

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21205
Approved symbol	LINGO1
Name	leucine rich repeat and Ig domain containing 1
Location	15q24.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ14594, LERN1
Ensembl gene	ENSG00000169783
Ensembl biotype	protein_coding
OMIM	609791
Entrez	84894

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000355300, ENST00000557798, ENST00000559893, ENST00000561030, ENST00000561686, ENST00000562933, ENST00000563316, ENST00000564066, ENST00000564472, ENST00000566711, ENST00000567605, ENST00000567726, ENST00000568951, ENST00000570216

RefSeq mRNA: 12 — MANE Select: NM_032808 NM_001301186, NM_001301187, NM_001301189, NM_001301191, NM_001301192, NM_001301194, NM_001301195, NM_001301197, NM_001301198, NM_001301199, NM_001301200, NM_032808

CCDS: CCDS45313, CCDS73766

Canonical transcript exons

ENST00000355300 — 2 exons

Exon	Start	End
ENSE00001430143	77613027	77615900
ENSE00001700105	77632310	77632912

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 98.98.

FANTOM5 (CAGE): breadth broad, TPM avg 9.4786 / max 370.1308, expressed in 640 samples.

FANTOM5 promoters (28 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151065	3.8674	526
151079	0.8896	139
151061	0.6204	224
151075	0.5548	146
151064	0.4803	196
151052	0.4574	184
151076	0.4134	124
151068	0.3061	101
151066	0.1923	84
151062	0.1682	101

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	98.98	gold quality
prefrontal cortex	UBERON:0000451	97.09	gold quality
right frontal lobe	UBERON:0002810	96.45	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.14	gold quality
frontal cortex	UBERON:0001870	96.13	gold quality
neocortex	UBERON:0001950	95.67	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.66	gold quality
anterior cingulate cortex	UBERON:0009835	95.47	gold quality
occipital lobe	UBERON:0002021	95.25	gold quality
cerebral cortex	UBERON:0000956	95.16	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.05	gold quality
amygdala	UBERON:0001876	94.78	gold quality
primary visual cortex	UBERON:0002436	94.50	gold quality
temporal lobe	UBERON:0001871	94.35	gold quality
middle temporal gyrus	UBERON:0002771	94.15	gold quality
entorhinal cortex	UBERON:0002728	93.20	gold quality
Ammon’s horn	UBERON:0001954	93.19	gold quality
superior frontal gyrus	UBERON:0002661	93.08	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.64	gold quality
Brodmann (1909) area 46	UBERON:0006483	92.18	gold quality
endothelial cell	CL:0000115	91.98	gold quality
parietal lobe	UBERON:0001872	91.59	gold quality
substantia nigra pars reticulata	UBERON:0001966	91.17	gold quality
substantia nigra pars compacta	UBERON:0001965	90.50	gold quality
hypothalamus	UBERON:0001898	90.25	gold quality
dorsal plus ventral thalamus	UBERON:0001897	90.21	gold quality
postcentral gyrus	UBERON:0002581	90.21	gold quality
forebrain	UBERON:0001890	89.68	gold quality
ventral tegmental area	UBERON:0002691	89.68	gold quality
substantia nigra	UBERON:0002038	89.28	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-2	no	11052.64
E-ANND-3	no	2.08

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CUX1, E2F1

miRNA regulators (miRDB)

82 targeting LINGO1, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6077	99.99	68.04	2299
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-7162-3P	99.89	68.16	1682

Literature-anchored findings (GeneRIF, showing 40)

• The LERN1 expression pattern is specific to the central nervous system, highly and broadly expressed during early stages of development and gradually restricted to forebrain structures as development proceeds(LERN1) (PMID:14686891)
• the Lingo-1 ectodomain is a module implicated in central nervous system repair inhibition (PMID:17005555)
• the ternary complex of NgR/TROY/LINGO-1 expressed on astrocytes, macrophages/microglia and neurones, by interacting with Nogo-A on oligodendrocytes, might modulate glial-neuronal interactions in demyelinating lesions of multiple sclerosis (PMID:17239012)
• inhibitory agents of LINGO-1 activity can protect dopaminergic neurons against degeneration (PMID:17726113)
• Variant in the sequence of the LINGO1 gene confers risk of essential tremor. (PMID:19182806)
• Quick identification of essential N-glycosylation sites of a heavily glycosylated neuroglycoprotein Lingo-1, which are sufficient for the support of its surface expression. (PMID:19254717)
• WNK1 is a novel signaling molecule involved in regulation of LINGO-1 mediated inhibition of neurite extension. (PMID:19363035)
• the LINGO1 gene is associated with an increased risk for essential tremor (PMID:19553813)
• Thisdy demonstrateda significant association between LINGO1 rs9652490 and essential tremor (P = 0.014) and Parkinson disease (P = 0.0003), thus providing the first evidence of a genetic link between both diseases. (PMID:19720553)
• LINGO1 variant increases risk of familial essential tremor. (PMID:19805735)
• In this study, SNPs rs9652490, rs11856808, and rs7177008 of LINGO1 were genotyped in a total of 694 Austrian subjects (349 PD, 345 controls). No association could be found between genotype or allele counts and Parkinson disease. (PMID:19908305)
• LINGO1 SNP (rs9652490) is not associated with sporadic PD in our Polish cohort. (PMID:20117178)
• Our study gives further evidence that LINGO1 acts as a susceptibility gene for essential tremor. (PMID:20310002)
• LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease (PMID:20369371)
• The LINGO1 gene is a risk factor for essential tremor in a Caucasian population in North America. (PMID:20372186)
• The two markers rs9652490 and rs11856808 were not strongly related to the essential tremor,late onset sporadic Parkinson’s disease, but the rs9652490G allele might be a protective factor for the early onset Parkinson’s disease in Chinese population. (PMID:20600614)
• LINGO-1 inhibits multiple aspects of oligodendrocyte differentiation independently of the LRRs via a process that requires p75(NTR) signalling (PMID:20659559)
• No significant differences are found in genotype and allele distribution in the rs9652490 variant of LINGO1 in either Chinese or Caucasian Parkinson disease patients. (PMID:20951767)
• LINGO1 variant rs9652490 (A > G) is unlikely to play a major role in Parkinson’s disease in Chinese populations. (PMID:20957646)
• while there were no significant differences in the Lingo1 minor allele frequency and genotype frequency between Chinese essential tremor and controls, pooled analysis showed a higher proportion of GG genotype in tremor patients (PMID:21158743)
• LINGO1 variants are not a major risk factor for developing familial essential tremor in this population, which suggests the existence of other genetic risk factors responsible for familial essential tremor in this movement disorder clinic population. (PMID:21219542)
• genotyping results lead us to conclude that no association exists between the key variant rs9652490 and Essential tremor (P(corr) = 1.00). (PMID:21264305)
• This study demonistrated that LINGO1 variants could increase risk of PD, specifically those presenting the non-rigid-akinetic phenotypes, which suggests that LINGO1 may have a role in the etiology of tremor in PD at least in the Spanish population. (PMID:21506150)
• There were no significant differences in frequencies for all alleles between the essential tremor (ET) group and controls; however, an association of genotype A/G of the SNP rs9652490 with the familial ET phenotype was found. (PMID:21741293)
• Single nucleotide polymorphism(SNP)s of LINGO1 play a role in the development of Parkinson’s disease in the Italian population. (PMID:21752692)
• This study showed that LINGO1 rs9652490 and rs11856808 are not associated with the risk of Parkinson’s disease. (PMID:21955595)
• the N-terminal region containing the leucine-rich repeats along with the transmembrane and cytoplasmic domains of LINGO-1 are not required for self-interaction or interaction with amyloid precursor protein (PMID:22133804)
• Results of a meta-analysis suggest a relationship between LINGO1 rs11856808 polymorphism and risk of essential tremor (ET) and familial ET, while rs9652490 polymorphism is only associated with the risk for familial ET. (PMID:22425540)
• LINGO-1, a transmembrane signaling protein, inhibits oligodendrocyte differentiation and myelination through intercellular self-interactions (PMID:22514275)
• the present meta-analysis does not support the notion that LINGO1 rs9652490 SNP is a major genetic risk factor for parkinson disease.[meta-analysis] (PMID:22710005)
• LINGO-1 potentiates neuronal apoptosis, likely by inhibiting WNK3 kinase activity. (PMID:23482566)
• This study demonistrated that theLINGO1 rs9652490 and rs11856808 polymorphisms are not associated with risk for multiple sclerosis. (PMID:23574883)
• This review found that several gene variants in the LINGO1 gene may increase the risk of essential tremor. (PMID:23682623)
• LINGO1 variants are associated with essential tremor in Chinese Han female patients. (PMID:23754655)
• Lingo-1 signaling is altered in the schizophrenia brain. (PMID:24448210)
• The results of this study show Increased LINGO1 in the cerebellum of essential tremor patients. (PMID:24531928)
• LINGO-1 can directly bind to ErbB2, block ErbB2 translocation into lipid rafts, and inhibit its phosphorylation. (PMID:24583087)
• Data indicate that leucine-rich repeat neuronal protein 1 (LINGO-1) is intracellular and competes with Nogo-66 receptor (NgR) for binding to p75 neurotrophin receptor (p75NTR). (PMID:25666623)
• LINGO1 rs11856808 plays a protective role by decreasing the risk for PD, but not for MSA, in Chinese population. (PMID:26254004)
• LINGO1 protein acts as a gateway protein internalizing into the tumor cells when engaged by antibody and can carry antibody conjugated with drugs to kill Ewing sarcoma cells. (PMID:26979953)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lingo1a	ENSDARG00000034165
danio_rerio	lingo1b	ENSDARG00000035899
mus_musculus	Lingo1	ENSMUSG00000049556
rattus_norvegicus	Lingo1	ENSRNOG00000017193

Paralogs (25): SLITRK3 (ENSG00000121871), LRFN3 (ENSG00000126243), LRFN1 (ENSG00000128011), SLIT2 (ENSG00000145147), LRFN2 (ENSG00000156564), LRRC38 (ENSG00000162494), SLITRK5 (ENSG00000165300), LRFN5 (ENSG00000165379), LRTM2 (ENSG00000166159), LRRN2 (ENSG00000170382), LRRN3 (ENSG00000173114), LRFN4 (ENSG00000173621), LINGO2 (ENSG00000174482), LRRN1 (ENSG00000175928), SLITRK1 (ENSG00000178235), GP5 (ENSG00000178732), SLITRK4 (ENSG00000179542), LRRC55 (ENSG00000183908), SLIT3 (ENSG00000184347), SLITRK6 (ENSG00000184564), SLITRK2 (ENSG00000185985), LRRC70 (ENSG00000186105), SLIT1 (ENSG00000187122), TLR9 (ENSG00000239732), TPBGL (ENSG00000261594)

Protein

Protein identifiers

Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 — Q96FE5 (reviewed: Q96FE5)

Alternative names: Leucine-rich repeat and immunoglobulin domain-containing protein 1, Leucine-rich repeat neuronal protein 1, Leucine-rich repeat neuronal protein 6A

All UniProt accessions (9): H0YMX3, H0YNK7, H3BM59, H3BMN3, H3BMW2, H3BN48, H3BQ49, H3BS32, Q96FE5

UniProt curated annotations — full annotation on UniProt →

Function. Functional component of the Nogo receptor signaling complex (RTN4R/NGFR) in RhoA activation responsible for some inhibition of axonal regeneration by myelin-associated factors. Is also an important negative regulator of oligodentrocyte differentiation and axonal myelination. Acts in conjunction with RTN4 and RTN4R in regulating neuronal precursor cell motility during cortical development.

Subunit / interactions. Homotetramer. Forms a ternary complex with RTN4R/NGFR and RTN4R/TNFRSF19. Interacts with NGRF and MYT1L. Interacts with RTN4R.

Subcellular location. Cell membrane.

Tissue specificity. Expressed exclusively in the central nervous system. Highest level in the in amygdala, hippocampus, thalamus and cerebral cortex. In the rest of the brain a basal expression seems to be always present. Up-regulated in substantia nigra neurons from Parkinson disease patients.

Post-translational modifications. N-glycosylated. Contains predominantly high-mannose glycans.

Disease relevance. Intellectual developmental disorder, autosomal recessive 64 (MRT64) [MIM:618103] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT64 patients have moderate to severe intellectual disability, delayed motor development, aggressive behavior, and slurred or absent speech. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The intracellular domain of LINGO1 interacts with MYT1L.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96FE5-1	1	yes
Q96FE5-2	2

RefSeq proteins (12): NP_001288115, NP_001288116, NP_001288118, NP_001288120, NP_001288121, NP_001288123, NP_001288124, NP_001288126, NP_001288127, NP_001288128, NP_001288129, NP_116197* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000372	LRRNT	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: PF07679, PF13855

UniProt features (88 total): strand 26, repeat 11, glycosylation site 10, helix 9, turn 8, sequence conflict 6, disulfide bond 5, domain 3, sequence variant 3, topological domain 2, signal peptide 1, chain 1, modified residue 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2ID5	X-RAY DIFFRACTION	2.7
4OQT	X-RAY DIFFRACTION	3.23

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96FE5-F1	86.59	0.77

Antibody-complex structures (SAbDab): 1 — 4OQT

Functional residue map

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

Post-translational modifications (1): 602

Disulfide bonds (5): 42–48, 46–57, 373–396, 375–421, 446–497

Glycosylation sites (10): 144, 202, 264, 274, 293, 341, 492, 505, 526, 542

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-193634	Axonal growth inhibition (RHOA activation)
R-HSA-162582	Signal Transduction
R-HSA-193697	p75NTR regulates axonogenesis
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-73887	Death Receptor Signaling

MSigDB gene sets: 132 (showing top): STAEGE_EWING_FAMILY_TUMOR, PEREZ_TP63_TARGETS, GOBP_NEUROGENESIS, BENPORATH_NOS_TARGETS, GOMF_SIGNALING_RECEPTOR_BINDING, CTTTGTA_MIR524, MODULE_207, RIGGI_EWING_SARCOMA_PROGENITOR_UP, YAMASHITA_LIVER_CANCER_STEM_CELL_UP, BENPORATH_OCT4_TARGETS, GOMF_EPIDERMAL_GROWTH_FACTOR_RECEPTOR_BINDING, GOMF_GROWTH_FACTOR_RECEPTOR_BINDING, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, REACTOME_P75NTR_REGULATES_AXONOGENESIS, REACTOME_DEATH_RECEPTOR_SIGNALING

GO Biological Process (1): neuron development (GO:0048666)

GO Molecular Function (3): epidermal growth factor receptor binding (GO:0005154), signaling receptor activity (GO:0038023), protein binding (GO:0005515)

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

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
p75NTR regulates axonogenesis	1
p75 NTR receptor-mediated signalling	1
Death Receptor Signaling	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
neuron differentiation	1
cell development	1
growth factor receptor binding	1
molecular transducer activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2250 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LINGO1	TNFRSF19	Q9NS68	996
LINGO1	NGFR	P08138	995
LINGO1	RTN4R	Q9BZR6	989
LINGO1	RTN4	Q9NQC3	982
LINGO1	MAG	P20916	878
LINGO1	RHOA	P06749	809
LINGO1	OMG	P23515	750
LINGO1	MYOC	Q99972	695
LINGO1	SORT1	Q99523	552
LINGO1	STK32B	Q9NY57	543
LINGO1	MBP	P02686	526
LINGO1	IGSF1	Q8N6C5	507
LINGO1	MYT1L	Q9UL68	505
LINGO1	OLIG2	Q13516	498
LINGO1	CNP	P09543	492

IntAct

81 interactions, top by confidence:

A	B	Type	Score
SLC27A6	TTC4	psi-mi:“MI:0914”(association)	0.640
NGFR	LINGO1	psi-mi:“MI:0915”(physical association)	0.590
LINGO1	NGFR	psi-mi:“MI:0915”(physical association)	0.590
LINGO1	TRIM27	psi-mi:“MI:0915”(physical association)	0.560
LINGO1	GOLGA2	psi-mi:“MI:0915”(physical association)	0.560
LINGO1	SPAG5	psi-mi:“MI:0915”(physical association)	0.560
GOLGA2	LINGO1	psi-mi:“MI:0915”(physical association)	0.560
SPAG5	LINGO1	psi-mi:“MI:0915”(physical association)	0.560
LINGO1	HSD3B7	psi-mi:“MI:0915”(physical association)	0.560
LINGO1	NTM	psi-mi:“MI:0915”(physical association)	0.560
	LINGO1	psi-mi:“MI:0915”(physical association)	0.560
LINGO1	KRTAP9-2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-9	LINGO1	psi-mi:“MI:0915”(physical association)	0.560
FRS3	LINGO1	psi-mi:“MI:0915”(physical association)	0.560
FBLN1	LINGO1	psi-mi:“MI:0915”(physical association)	0.560
MACO1	LINGO1	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-6	LINGO1	psi-mi:“MI:0915”(physical association)	0.560
APP	LINGO1	psi-mi:“MI:0915”(physical association)	0.560
LINGO1	LINGO2	psi-mi:“MI:0915”(physical association)	0.560
LINGO1	Rtn4r	psi-mi:“MI:0407”(direct interaction)	0.540
Rtn4r	LINGO1	psi-mi:“MI:0915”(physical association)	0.540
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LRFN4	RIMOC1	psi-mi:“MI:0914”(association)	0.530
ACAD9	PPL	psi-mi:“MI:0914”(association)	0.530

BioGRID (70): LINGO1 (Two-hybrid), LINGO1 (Two-hybrid), LINGO1 (Two-hybrid), LINGO1 (Affinity Capture-MS), LINGO1 (Two-hybrid), LINGO1 (Two-hybrid), LINGO2 (Affinity Capture-MS), HIST2H2AC (Affinity Capture-MS), LINGO1 (Affinity Capture-MS), LMAN2L (Affinity Capture-MS), LINGO1 (Affinity Capture-MS), LINGO1 (Affinity Capture-MS), C4orf32 (Affinity Capture-MS), PON2 (Affinity Capture-MS), LINGO1 (Affinity Capture-MS)

ESM2 similar proteins: A0N0X6, A4IIW9, B0BLW3, B1H134, B1H234, B4F7C5, D3ZAL8, D3ZTV3, D4A7P2, E5DHB5, F1NUK7, F7D3V9, O43155, O43300, O94898, P58681, Q32Q07, Q3SXY7, Q3URE9, Q504C1, Q50L44, Q52KR2, Q5R482, Q5R6T0, Q5RDJ4, Q61809, Q66HV9, Q6RKD8, Q6UXK5, Q70AK3, Q7L985, Q80XG9, Q80ZD7, Q80ZD8, Q80ZD9, Q86VH4, Q86VH5, Q8BGA3, Q8BGT1, Q8BLU0

Diamond homologs: A0A140LHF2, P0DP72, P11464, P16573, P31809, P31997, P35329, Q00887, Q15223, Q15746, Q16557, Q58EX2, Q6V4S5, Q96FE5, Q9D1T0, Q9GL76, Q9N008, A0A1Y9G8H0, A0A452E9Y6, A1KZ92, A2A8L5, A2AJ76, A4IFW2, A4IGL7, A4IIW9, A5JUY8, A7MBJ4, A8WGA3, A8WQH2, B0BNK7, B3A0P3, D2HFT7, D3YXG0, D4A1J9, D4ABX8, G5EBF1, G5EG78, H2A0M7, O15146, O35158

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
OMG	up-regulates	LINGO1	binding
RTN4	up-regulates	LINGO1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	88
Likely benign	32
Benign	8

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
560183	NM_032808.7(LINGO1):c.869G>A (p.Arg290His)	Pathogenic
560184	NM_032808.7(LINGO1):c.863A>G (p.Tyr288Cys)	Pathogenic

SpliceAI

239 predictions. Top by Δscore:

Variant	Effect	Δscore
15:77632305:CTCA:C	donor_loss	0.9900
15:77632306:TCA:T	donor_loss	0.9900
15:77632307:CACC:C	donor_loss	0.9900
15:77632308:A:C	donor_loss	0.9900
15:77615908:C:T	acceptor_gain	0.9800
15:77632304:GCTCA:G	donor_loss	0.9700
15:77632309:CCTG:C	donor_gain	0.9700
15:77615909:G:T	acceptor_gain	0.9600
15:77632308:A:AC	donor_gain	0.9600
15:77632309:C:CC	donor_gain	0.9600
15:77632418:T:TA	donor_gain	0.9500
15:77615908:C:CT	acceptor_gain	0.9400
15:77615898:CAC:C	acceptor_gain	0.9300
15:77615898:CACCT:C	acceptor_loss	0.9300
15:77615899:ACCTG:A	acceptor_loss	0.9300
15:77615901:CT:C	acceptor_loss	0.9300
15:77615902:T:A	acceptor_loss	0.9300
15:77615918:C:CT	acceptor_gain	0.9300
15:77615896:CTCAC:C	acceptor_gain	0.9200
15:77632415:T:TA	donor_gain	0.9200
15:77615914:C:CT	acceptor_gain	0.9100
15:77615905:A:T	acceptor_gain	0.8800
15:77615915:A:T	acceptor_gain	0.8800
15:77632421:T:TA	donor_gain	0.8800
15:77632424:TCCGA:T	donor_gain	0.8800
15:77632425:CCGAC:C	donor_gain	0.8800
15:77632406:T:TA	donor_gain	0.8500
15:77615903:G:C	acceptor_loss	0.8300
15:77632433:T:TA	donor_gain	0.8200
15:77632312:G:A	donor_gain	0.8100

AlphaMissense

4035 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:77614180:A:G	L576P	1.000
15:77614184:A:G	C575R	1.000
15:77614199:C:G	G570R	1.000
15:77614203:G:C	F568L	1.000
15:77614203:G:T	F568L	1.000
15:77614205:A:G	F568L	1.000
15:77614217:C:G	G564R	1.000
15:77614416:G:C	C497W	1.000
15:77614417:C:G	C497S	1.000
15:77614418:A:T	C497S	1.000
15:77614424:A:C	Y495D	1.000
15:77614462:A:G	L482P	1.000
15:77614533:C:A	W458C	1.000
15:77614533:C:G	W458C	1.000
15:77614535:A:G	W458R	1.000
15:77614535:A:T	W458R	1.000
15:77615448:G:C	N153K	1.000
15:77615448:G:T	N153K	1.000
15:77615449:T:A	N153I	1.000
15:77615464:A:G	L148P	1.000
15:77615592:G:C	N105K	1.000
15:77615592:G:T	N105K	1.000
15:77614182:G:C	C575W	0.999
15:77614183:C:T	C575Y	0.999
15:77614189:A:G	L573P	0.999
15:77614189:A:T	L573H	0.999
15:77614198:C:T	G570D	0.999
15:77614201:A:G	L569P	0.999
15:77614216:C:T	G564D	0.999
15:77614228:G:T	A560D	0.999

dbSNP variants (sampled 300 via entrez): RS1000002354 (15:77615381 C>G,T), RS1000010605 (15:77693832 C>G,T), RS1000032442 (15:77752815 C>A), RS1000041754 (15:77693538 C>T), RS1000052402 (15:77655844 C>T), RS1000060025 (15:77645509 G>A), RS1000067353 (15:77684444 C>T), RS1000084796 (15:77803856 C>G,T), RS1000128113 (15:77690372 G>GC), RS1000133949 (15:77683227 A>G), RS1000151209 (15:77735614 C>G), RS1000175061 (15:77649973 T>A), RS1000224817 (15:77787505 T>C), RS1000229184 (15:77801007 T>C,G), RS1000245170 (15:77766376 C>A)

Disease associations

OMIM: gene MIM:609791 | disease phenotypes: MIM:618103

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal recessive 64	Moderate	Autosomal recessive

Mondo (1): intellectual disability, autosomal recessive 64 (MONDO:0020846)

Orphanet (0):

HPO phenotypes

14 total (14 of 14 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000718	Aggressive behavior
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001344	Absent speech
HP:0001350	Slurred speech
HP:0003593	Infantile onset
HP:0010864	Severe intellectual disability
HP:0011968	Feeding difficulties
HP:0012760	Reduced social responsiveness

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000329_1	Essential tremor	1.000000e-09
GCST001365_2	Anticoagulant levels	7.000000e-06
GCST003770_31	Neuroticism	3.000000e-08
GCST004956_2	Risky sexual behaviors (alcohol dependence interaction)	4.000000e-08
GCST005316_498	Intelligence (MTAG)	4.000000e-08
GCST006001_3	Hemoglobin A1c levels	1.000000e-08
GCST006943_16	Feeling miserable	6.000000e-09
GCST007709_134	General factor of neuroticism	3.000000e-08
GCST008595_94	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	1.000000e-10
GCST009524_146	Household income (MTAG)	1.000000e-12
GCST009524_279	Household income (MTAG)	3.000000e-09
GCST009524_88	Household income (MTAG)	2.000000e-08
GCST010988_207	Adult body size	3.000000e-09
GCST011096_33	Systemic lupus erythematosus	2.000000e-08
GCST011126_28	Caffeine consumption from coffee or tea	3.000000e-09
GCST011348_37	High density lipoprotein cholesterol levels	7.000000e-09
GCST011693_11	Triglyceride levels	6.000000e-07

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004637	protein S measurement
EFO:0007660	neuroticism measurement
EFO:0004337	intelligence
EFO:0004541	HbA1c measurement
EFO:0009598	feeling miserable measurement
EFO:0004784	self reported educational attainment
EFO:0009695	household income
EFO:0006781	coffee consumption measurement
EFO:0010091	tea consumption measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712965 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Reticulons and associated proteins

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
opicinumab	Binding	9.96	pEC50

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression	2
Valproic Acid	decreases expression, increases methylation	2
methylmercuric chloride	increases expression	1
propionaldehyde	increases expression	1
testosterone undecanoate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, decreases expression	1
pentanal	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
ormosil	affects binding, increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	decreases expression	1
Aldehydes	increases expression	1
Benzo(a)pyrene	affects methylation	1
Calcitriol	increases expression	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Malathion	decreases expression	1
Methapyrilene	increases methylation	1
Niclosamide	increases expression	1

Clinical trials (associated diseases)

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