LYNX1

Summary

LYNX1 (Ly6/neurotoxin 1, HGNC:29604) is a protein-coding gene on chromosome 8q24.3, encoding Ly-6/neurotoxin-like protein 1 (P0DP58). Acts in different tissues through interaction to nicotinic acetylcholine receptors (nAChRs).

This gene encodes a GPI-anchored, cell membrane bound member of the Ly6/uPAR (LU) superfamily of proteins containing the unique three-finger LU domain. This protein interacts with nicotinic acetylcholine receptors (nAChRs), and is thought to function as a modulator of nAChR activity to prevent excessive excitation. Alternatively spliced transcript variants have been found for this gene. Read-through transcription between this gene and the neighboring downstream gene (SLURP2) generates naturally-occurring transcripts (LYNX1-SLURP2) that encode a fusion protein comprised of sequence sharing identity with each individual gene product.

Source: NCBI Gene 66004 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 16 total
• MANE Select transcript: NM_177477

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29604
Approved symbol	LYNX1
Name	Ly6/neurotoxin 1
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	SLURP2
Ensembl gene	ENSG00000180155
Ensembl biotype	protein_coding
OMIM	606110
Entrez	66004

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 10 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000522906, ENST00000613110, ENST00000614268, ENST00000614491, ENST00000620006, ENST00000621401, ENST00000652477, ENST00000897364, ENST00000897365, ENST00000897366, ENST00000897367

RefSeq mRNA: 4 — MANE Select: NM_177477 NM_001356370, NM_177457, NM_177476, NM_177477

CCDS: CCDS6389

Canonical transcript exons

ENST00000652477 — 4 exons

Exon	Start	End
ENSE00003848532	142777106	142777202
ENSE00003850875	142771202	142775363
ENSE00003889828	142775906	142776121
ENSE00003890314	142775593	142775694

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 97.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.2968 / max 795.9825, expressed in 970 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95427	15.2562	970
95429	2.1620	764
95428	0.0406	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	97.46	gold quality
right frontal lobe	UBERON:0002810	97.46	gold quality
prefrontal cortex	UBERON:0000451	97.05	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.37	gold quality
frontal cortex	UBERON:0001870	96.04	gold quality
anterior cingulate cortex	UBERON:0009835	96.04	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.93	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.65	gold quality
heart left ventricle	UBERON:0002084	95.02	gold quality
neocortex	UBERON:0001950	94.99	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.86	gold quality
cardiac ventricle	UBERON:0002082	94.78	gold quality
amygdala	UBERON:0001876	94.52	gold quality
Ammon’s horn	UBERON:0001954	94.36	gold quality
hypothalamus	UBERON:0001898	94.27	gold quality
cerebral cortex	UBERON:0000956	94.14	gold quality
right atrium auricular region	UBERON:0006631	94.12	gold quality
left ventricle myocardium	UBERON:0006566	94.06	gold quality
cardiac atrium	UBERON:0002081	93.85	gold quality
cerebellar hemisphere	UBERON:0002245	93.68	gold quality
cerebellar cortex	UBERON:0002129	93.65	gold quality
pons	UBERON:0000988	93.23	gold quality
cerebellum	UBERON:0002037	92.98	gold quality
temporal lobe	UBERON:0001871	92.88	gold quality
superior frontal gyrus	UBERON:0002661	92.77	gold quality
putamen	UBERON:0001874	92.71	gold quality
parietal lobe	UBERON:0001872	92.70	gold quality
heart	UBERON:0000948	92.40	gold quality
forebrain	UBERON:0001890	92.33	gold quality
postcentral gyrus	UBERON:0002581	92.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.51

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

103 targeting LYNX1, 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-4283	100.00	66.42	2097
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-1915-3P	99.58	66.79	1988

Literature-anchored findings (GeneRIF, showing 13)

• LY-6K,a novel member protein of the Ly-6/uPAR superfamily, is a significant new molecular marker for diagnosis and gene therapy in patients with breast cancer. (PMID:17089039)
• decreased Lynx1 is associated with squamous cell lung carcinoma (PMID:18559515)
• LY-6K meaningfully participates in breast cancer cell metastasis (PMID:19639180)
• Computer modeling, based on ws-LYNX1 NMR structure and AChBP x-ray structure, revealed a possible mode of ws-LYNX1 binding. (PMID:21252236)
• Micromolar affinities and fast washout rates measured for ws-LYNX1 and its mutants are in contrast to nanomolar affinities and irreversibility of binding for alpha-bungarotoxin and similar snake alpha-neurotoxins also targeting alpha7 nAChR. (PMID:23585571)
• This epigenome-wide DNA methylation analysis in postmortem hippocampus and prefrontal cortex specimens confirmed LYNX1 DNA methylation profiles in major depression. (PMID:25571874)
• These studies suggest that lynx1 is a potential target both for development of drugs that may limit lung cancer growth as well as for drugs that may be effective for asthma or COPD treatment. (PMID:26025503)
• These findings provide new insights into the acetylcholine receptor-mediated regulatory mechanism of SLURP-2 expression in keratinocytes. (PMID:26033490)
• results show that some functional and behavioral aspects of alpha6-nAChRs are modulated by lynx1 (PMID:29206881)
• The ability of ws-Lynx1 to regulate homeostasis of epithelial cancer cells. (PMID:31150435)
• Increased Expression of LYNX1 in Ovarian Serous Cystadenocarcinoma Predicts Poor Prognosis. (PMID:33299855)
• Spatial Structure and Activity of Synthetic Fragments of Lynx1 and of Nicotinic Receptor Loop C Models. (PMID:33374963)
• Lynx1 and the family of endogenous mammalian neurotoxin-like proteins and their roles in modulating nAChR function. (PMID:37437646)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Slurp2	ENSMUSG00000075605
rattus_norvegicus	Slurp2	ENSRNOG00000031437
caenorhabditis_elegans	D1081.20	WBGENE00304985

Paralogs (1): LY6D (ENSG00000167656)

Protein

Protein identifiers

Ly-6/neurotoxin-like protein 1 — P0DP58 (reviewed: P0DP58)

Alternative names: Endogenous prototoxin LYNX1, Testicular tissue protein Li 112

All UniProt accessions (3): P0DP58, A0A087WYG6, A0A087WZS0

UniProt curated annotations — full annotation on UniProt →

Function. Acts in different tissues through interaction to nicotinic acetylcholine receptors (nAChRs). The proposed role as modulator of nAChR activity seems to be dependent on the nAChR subtype and stoichiometry, and to involve an effect on nAChR trafficking and its cell surface expression, and on single channel properties of the nAChR inserted in the plasma membrane. Modulates functional properties of nicotinic acetylcholine receptors (nAChRs) to prevent excessive excitation, and hence neurodegeneration. Enhances desensitization by increasing both the rate and extent of desensitization of alpha-4:beta-2-containing nAChRs and slowing recovery from desensitization. Promotes large amplitude ACh-evoked currents through alpha-4:beta-2 nAChRs. Is involved in regulation of the nAChR pentameric assembly in the endoplasmic reticulum. Shifts stoichiometry from high sensitivity alpha-4(2):beta-2(3) to low sensitivity alpha-4(3):beta-2(2) nAChR. In vitro modulates alpha-3:beta-4-containing nAChRs. Reduces cell surface expression of (alpha-3:beta-4)(2):beta-4 and (alpha-3:beta-4)(2):alpha-5 nAChRs suggesting an interaction with nAChR alpha-3(-):(+)beta-4 subunit interfaces and an allosteric mode. Corresponding single channel effects characterized by decreased unitary conductance, altered burst proportions and enhanced desensitization/inactivation seem to depend on nAChR alpha:alpha subunit interfaces and are greater in (alpha-3:beta-2)(2):alpha-3 when compared to (alpha-3:beta-2)(2):alpha-5 nAChRs. Prevents plasticity in the primary visual cortex late in life.

Subunit / interactions. Interacts with nAChRs containing alpha-4:beta-2 (CHRNA4:CHRNB2) and alpha-7 (CHRNA7) subunits. Interacts with CHRNA4 probably in the endoplasmic reticulum prior to nAChR pentameric assembly. Interacts with KCNA2/Potassium voltage-gated channel subfamily A member 2.

Subcellular location. Cell membrane. Cell projection. Dendrite. Endoplasmic reticulum.

Miscellaneous. Isoform 1 is considered to be an endogenous ‘prototoxin’, that shares a N-terminal three-finger structure with snake alpha-neurotoxins. Based on a naturally occurring readthrough transcript which produces a LYNX1-SLURP2 fusion protein.

Isoforms (2)

UniProt ID	Names	Canonical?
P0DP58-1	1, LYNX1	yes
P0DP58-2	2, LYNX1-SLURP2

RefSeq proteins (4): NP_001343299, NP_803252, NP_803429, NP_803430* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016054	LY6_UPA_recep-like	Domain
IPR035076	Toxin/TOLIP	Domain
IPR045860	Snake_toxin-like_sf	Homologous_superfamily
IPR051110	Ly-6/neurotoxin-like_GPI-ap	Family

Pfam: PF00087

UniProt features (19 total): strand 7, disulfide bond 5, signal peptide 1, chain 1, splice variant 1, turn 1, propeptide 1, domain 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2L03	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0DP58-F1	80.80	0.41

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): 91

Disulfide bonds (5): 23–46, 26–33, 39–64, 68–85, 86–91

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 103 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_SYNAPTIC_TRANSMISSION_CHOLINERGIC, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELL_CELL_SIGNALING, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, TGANTCA_AP1_C, GOBP_CELLULAR_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_SYNAPTIC_SIGNALING, GOBP_RESPONSE_TO_ACETYLCHOLINE, GOCC_NEURON_PROJECTION, GOBP_REGULATION_OF_NEUROTRANSMITTER_RECEPTOR_ACTIVITY, GOMF_SIGNALING_RECEPTOR_BINDING

GO Biological Process (3): synaptic transmission, cholinergic (GO:0007271), acetylcholine receptor signaling pathway (GO:0095500), regulation of neurotransmitter receptor activity (GO:0099601)

GO Molecular Function (4): ion channel inhibitor activity (GO:0008200), acetylcholine receptor regulator activity (GO:0030548), acetylcholine receptor inhibitor activity (GO:0030550), acetylcholine receptor binding (GO:0033130)

GO Cellular Component (7): endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), dendrite (GO:0030425), synapse (GO:0045202), side of membrane (GO:0098552), membrane (GO:0016020), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
acetylcholine receptor activity	3
cellular anatomical structure	3
membrane	2
chemical synaptic transmission	1
postsynaptic signal transduction	1
cellular response to acetylcholine	1
regulation of signaling receptor activity	1
neurotransmitter receptor activity	1
monoatomic ion channel activity	1
channel inhibitor activity	1
transmembrane transporter binding	1
ion channel regulator activity	1
neurotransmitter receptor regulator activity	1
signaling receptor inhibitor activity	1
acetylcholine receptor regulator activity	1
signaling receptor binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cell periphery	1
neuron projection	1
dendritic tree	1
cell junction	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

584 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LYNX1	SLURP1	P55000	964
LYNX1	LY6H	O94772	806
LYNX1	LYPD6	Q86Y78	778
LYNX1	LYPD2	Q6UXB3	776
LYNX1	LY6K	Q17RY6	736
LYNX1	CD59	P13987	713
LYNX1	PLAUR	Q03405	679
LYNX1	PLA2G1B	P04054	637
LYNX1	LYPD1	Q8N2G4	633
LYNX1	CHRNA1	P02708	629
LYNX1	GPIHBP1	Q8IV16	609
LYNX1	PATE4	P0C8F1	607
LYNX1	PSCA	O43653	605
LYNX1	LYPD6B	Q8NI32	601
LYNX1	SLURP2	P0DP57	580

IntAct

10 interactions, top by confidence:

A	B	Type	Score
ECE1	LYNX1	psi-mi:“MI:0915”(physical association)	0.370
LYNX1	CHRNB2	psi-mi:“MI:0914”(association)	0.350
LYNX1	APP	psi-mi:“MI:0914”(association)	0.350
LYNX1	Chrna3	psi-mi:“MI:0914”(association)	0.350
APP	Chrna3	psi-mi:“MI:0914”(association)	0.350
LYNX1	Chrna7	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	IGLON5	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0JNB3, A0JNL5, H3BJG9, H3BQJ8, O09108, O43653, O94772, O95867, P01231, P01232, P04651, P05533, P07434, P0CW03, P0DP58, P0DP62, P0DTL4, P35456, P49616, P57096, Q03405, Q05588, Q14210, Q14773, Q148C3, Q16553, Q1RMQ4, Q28216, Q28785, Q3UY51, Q4KLL3, Q4R5M8, Q5IS42, Q5R510, Q64253, Q6EV78, Q6IY74, Q6ZSA7, Q8HZR9, Q8IV16

Diamond homologs: O43653, P0DP58, P57096, Q16553, Q6UXB3, Q90986, P0DP60, P0DP62, Q1RMQ4, Q5IS42, Q5IS87, P0DP59

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	0
Likely pathogenic	0
Uncertain significance	11
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

522 predictions. Top by Δscore:

Variant	Effect	Δscore
8:142775690:CTGGG:C	acceptor_gain	1.0000
8:142775691:TGGG:T	acceptor_gain	1.0000
8:142775695:C:CC	acceptor_gain	1.0000
8:142775705:CAGA:C	acceptor_gain	1.0000
8:142775706:A:T	acceptor_gain	1.0000
8:142775708:A:AC	acceptor_gain	1.0000
8:142775708:A:C	acceptor_gain	1.0000
8:142775713:C:CT	acceptor_gain	1.0000
8:142775591:A:AC	donor_gain	0.9900
8:142775592:C:CC	donor_gain	0.9900
8:142775592:CAG:C	donor_gain	0.9900
8:142775693:GG:G	acceptor_gain	0.9900
8:142775701:T:C	acceptor_gain	0.9900
8:142775701:T:TC	acceptor_gain	0.9900
8:142775714:G:T	acceptor_gain	0.9900
8:142775927:C:CT	donor_gain	0.9900
8:142776120:CC:C	acceptor_gain	0.9900
8:142776121:CC:C	acceptor_gain	0.9900
8:142777103:CACC:C	donor_loss	0.9900
8:142777104:A:T	donor_loss	0.9900
8:142777105:C:CA	donor_loss	0.9900
8:142777105:CCTG:C	donor_gain	0.9900
8:142777107:TGTG:T	donor_gain	0.9900
8:142777118:C:CT	donor_gain	0.9900
8:142775585:AGAC:A	donor_loss	0.9800
8:142775586:GAC:G	donor_loss	0.9800
8:142775587:ACTCA:A	donor_loss	0.9800
8:142775588:CT:C	donor_loss	0.9800
8:142775589:TCACA:T	donor_loss	0.9800
8:142775590:C:CC	donor_loss	0.9800

AlphaMissense

742 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:142775332:C:A	K62N	0.995
8:142775332:C:G	K62N	0.995
8:142775331:A:G	S63P	0.994
8:142775598:C:G	R50P	0.988
8:142775246:C:G	C91S	0.986
8:142775247:A:T	C91S	0.986
8:142775315:C:G	C68S	0.986
8:142775316:A:T	C68S	0.986
8:142775327:C:G	C64S	0.986
8:142775328:A:T	C64S	0.986
8:142775333:T:G	K62T	0.986
8:142775609:G:C	C46W	0.986
8:142775631:C:G	C39S	0.986
8:142775632:A:T	C39S	0.986
8:142775670:C:G	C26S	0.986
8:142775671:A:T	C26S	0.986
8:142775316:A:G	C68R	0.985
8:142775610:C:T	C46Y	0.985
8:142775679:C:G	C23S	0.985
8:142775680:A:T	C23S	0.985
8:142775327:C:T	C64Y	0.984
8:142775334:T:C	K62E	0.984
8:142775649:C:G	C33S	0.984
8:142775650:A:T	C33S	0.984
8:142775242:G:C	N92K	0.983
8:142775242:G:T	N92K	0.983
8:142775328:A:G	C64R	0.982
8:142775610:C:G	C46S	0.982
8:142775611:A:T	C46S	0.982
8:142775632:A:G	C39R	0.982

dbSNP variants (sampled 300 via entrez): RS1000164389 (8:142777654 G>A), RS1000270374 (8:142772916 G>A,T), RS1000307501 (8:142779498 T>C), RS1000438331 (8:142774113 G>A), RS1000638647 (8:142778033 C>G), RS1001337475 (8:142777183 G>C), RS1002126971 (8:142771118 G>A), RS1002914003 (8:142772851 A>C), RS1002973298 (8:142777655 C>G,T), RS1003005703 (8:142777173 G>A), RS1003060450 (8:142775857 C>G,T), RS1003112923 (8:142771343 C>T), RS1003128231 (8:142772082 G>A), RS1003163789 (8:142771531 G>T), RS1003341372 (8:142775911 G>C)

Disease associations

OMIM: gene MIM:606110 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, decreases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
sodium arsenate	decreases expression, increases abundance	1
sodium arsenite	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
avobenzone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Agent Orange	decreases methylation, increases abundance	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Vehicle Emissions	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Defoliants, Chemical	increases abundance, decreases methylation	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Nitrosamines	decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression, increases abundance	1
Tetrachlorodibenzodioxin	decreases methylation, increases abundance	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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