NLGN1

Summary

NLGN1 (neuroligin 1, HGNC:14291) is a protein-coding gene on chromosome 3q26.31, encoding Neuroligin-1 (Q8N2Q7). Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.

This gene encodes a member of a family of neuronal cell surface proteins. Members of this family may act as splice site-specific ligands for beta-neurexins and may be involved in the formation and remodeling of central nervous system synapses.

Source: NCBI Gene 22871 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autism, susceptibility to, 20 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 15
• Clinical variants (ClinVar): 146 total
• Phenotypes (HPO): 6
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001365925

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14291
Approved symbol	NLGN1
Name	neuroligin 1
Location	3q26.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1070, NLG1
Ensembl gene	ENSG00000169760
Ensembl biotype	protein_coding
OMIM	600568
Entrez	22871

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000361589, ENST00000413821, ENST00000415045, ENST00000423427, ENST00000457714, ENST00000466350, ENST00000469564, ENST00000469727, ENST00000482120, ENST00000490929, ENST00000695368

RefSeq mRNA: 15 — MANE Select: NM_001365925 NM_001365923, NM_001365924, NM_001365925, NM_001365926, NM_001365927, NM_001365928, NM_001365929, NM_001365930, NM_001365931, NM_001365932, NM_001365933, NM_001365934, NM_001365935, NM_001365936, NM_014932

CCDS: CCDS3222, CCDS93427

Canonical transcript exons

ENST00000695368 — 7 exons

Exon	Start	End
ENSE00001148309	174278861	174279650
ENSE00001209527	173807680	173807832
ENSE00001512784	174280481	174294372
ENSE00001774137	173604279	173605091
ENSE00003484501	174275315	174275527
ENSE00003963539	173605534	173605593
ENSE00003963540	173397744	173398063

Expression profiles

Bgee: expression breadth ubiquitous, 216 present calls, max score 92.67.

FANTOM5 (CAGE): breadth broad, TPM avg 4.3988 / max 1133.9355, expressed in 700 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
39854	1.8851	583
39859	1.1005	222
39855	0.4784	70
39853	0.4612	238
39852	0.2733	84
39851	0.1907	106
39864	0.0097	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	92.67	gold quality
ventricular zone	UBERON:0003053	88.30	gold quality
endothelial cell	CL:0000115	87.51	silver quality
sural nerve	UBERON:0015488	87.34	gold quality
calcaneal tendon	UBERON:0003701	86.50	gold quality
ganglionic eminence	UBERON:0004023	85.14	gold quality
stromal cell of endometrium	CL:0002255	82.71	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.37	gold quality
buccal mucosa cell	CL:0002336	80.82	gold quality
entorhinal cortex	UBERON:0002728	80.78	gold quality
corpus callosum	UBERON:0002336	80.00	gold quality
primary visual cortex	UBERON:0002436	79.47	gold quality
prefrontal cortex	UBERON:0000451	79.15	gold quality
postcentral gyrus	UBERON:0002581	78.41	gold quality
superior frontal gyrus	UBERON:0002661	78.04	gold quality
Brodmann (1909) area 23	UBERON:0013554	77.74	gold quality
middle temporal gyrus	UBERON:0002771	77.38	gold quality
cerebellum	UBERON:0002037	77.30	gold quality
cerebellar vermis	UBERON:0004720	77.29	gold quality
colonic epithelium	UBERON:0000397	77.22	gold quality
cerebellar cortex	UBERON:0002129	76.89	gold quality
cerebral cortex	UBERON:0000956	76.78	gold quality
Ammon’s horn	UBERON:0001954	76.77	gold quality
cerebellar hemisphere	UBERON:0002245	76.75	gold quality
parietal lobe	UBERON:0001872	76.70	gold quality
frontal cortex	UBERON:0001870	76.67	gold quality
temporal lobe	UBERON:0001871	76.63	gold quality
right hemisphere of cerebellum	UBERON:0014890	76.61	gold quality
neocortex	UBERON:0001950	76.53	gold quality
islet of Langerhans	UBERON:0000006	76.52	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	6138.73
E-GEOD-131882	yes	2446.19
E-CURD-119	yes	2033.73
E-HCAD-35	yes	88.01
E-HCAD-25	yes	25.08
E-ANND-3	yes	6.10
E-GEOD-93593	yes	4.40
E-MTAB-4850	no	0.50

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DLX4, RORA, TCF3

miRNA regulators (miRDB)

204 targeting NLGN1, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 26)

• glycosylation processing of neuroligin, in addition to mRNA splicing and gene selection, contributes to the specificity of the neurexin-beta/neuroligin-1 association (PMID:14522992)
• the neurexin 1beta/neuroligin 1 complex has a role in synapse formation (PMID:15797875)
• Neuroligin mutations most probably represent rare causes of autism; it is unlikely that the allelic variants in any of these genes would be major risk factors for autism. (PMID:16077734)
• Our discoveries provide insight into the specific interaction of the GOPC PDZ domain with the C-terminal peptide of Nlg and also provide a general insight about the possible binding mode of the interaction of Nlg with other PDZ domain-containing proteins. (PMID:16882988)
• Neuroligin-1 performs diverse synaptic functions by mechanisms that include as essential components of alpha-neurexin binding and neuroligin dimerization, but extend beyond these activities. (PMID:19730411)
• Amyloid beta-peptide binds to the extracellular domain of neuroligin-1 with a K(d) in the nanomolar range. (PMID:21838267)
• Expression levels of neurexin and neuroligin in ENS are significantly down-regulated in HSCR, which may be involved in the pathogenesis of HSCR. (PMID:23264101)
• these manipulations of NL1 function illuminate the significance of NL1 intracellular signaling in vivo, and enhance our understanding of the factors that gate the maturation of glutamatergic synapses and complex behavior (PMID:23719805)
• Monitoring the attachment and detachment of neurexin (Nrx)-coated quantum dots measures the rates of neurexin (Nrx)/neuroligin interaction in the hippocampus. (PMID:23853109)
• We identified a cluster of single nucleotide polymorphisms at the NLGN1 locus showing significant association with BP variability. Follow-up analyses did not support an association with risk of ischemic stroke and its subtypes (PMID:23929743)
• Increasing expression of TGF-beta1 protein, decreasing expressions of Ghrelin, Neurexin, and Neuroligin proteins can induce the loss or dysfunction of ganglion cells in distal intestinal canal (PMID:25399301)
• the expression of NL1 and its binding partner neurexin-1beta was increased in temporal lobe epileptic foci in patients and lithium-pilocarpine-treated epileptic rats. (PMID:25428619)
• Results indicate that the neurexin and neuroligin synaptic complex is intrinsically involved in the regulation of DISC1 function, thus contributing to a better understanding of the pathology of schizophrenia. (PMID:26078884)
• Neuroligin-1 and Glu may represent new markers of ganglion cells, whose expression may correlate with the pathogenesis, diagnosis, differential diagnosis or classification of Hirschsprung’s disease. (PMID:26109803)
• Neuroligin 1 (NL1) promotes the formation of glutamatergic synapses and mediates long-term potentiation. (PMID:26440732)
• NLGN1 was associated with schizophrenia in Chinese Han Populations (PMID:26674772)
• Findings support a contribution of the NLGN1 gene pathway to the neurobiological underpinnings of PTSD. (PMID:27219346)
• We show that a novel NLGN1 Pro89Leu (P89L) missense variant found in two autism spectrum disorder (ASD) siblings leads to changes in cellular localization, protein degradation, and to the impairment of spine formation. Furthermore, we generated the knock-in P89L mice, and we show that the P89L heterozygote mice display abnormal social behavior, a core feature of ASD (PMID:28841651)
• we propose that this homozygous variant in NLGN1 can be the cause of the ASD/ID of these brothers although functional studies and/or model systems will be necessary to provide evidence for its pathogenicity. (PMID:30460678)
• TSPAN5 Enriched Microdomains Provide a Platform for Dendritic Spine Maturation through Neuroligin-1 Clustering. (PMID:31665629)
• Synaptic Kalirin-7 and Trio Interactomes Reveal a GEF Protein-Dependent Neuroligin-1 Mechanism of Action. (PMID:31801062)
• Neuroligin-1 in brain and CSF of neurodegenerative disorders: investigation for synaptic biomarkers. (PMID:33522967)
• Upregulated NLGN1 predicts poor survival in colorectal cancer. (PMID:34340665)
• Prenatal glucocorticoid exposure selectively impairs neuroligin 1-dependent neurogenesis by suppressing astrocytic FGF2-neuronal FGFR1 axis. (PMID:35562616)
• The neuronal protein Neuroligin 1 promotes colorectal cancer progression by modulating the APC/beta-catenin pathway. (PMID:36056393)
• Association between Neuroligin-1 polymorphism and plasma glutamine levels in individuals with autism spectrum disorder. (PMID:37544204)

Cross-species orthologs

45 orthologs

Organism	Symbol	Gene ID
danio_rerio	nlgn1	ENSDARG00000077710
mus_musculus	Nlgn1	ENSMUSG00000063887
rattus_norvegicus	Nlgn1	ENSRNOG00000032576
drosophila_melanogaster	Est-6	FBGN0000592
drosophila_melanogaster	Est-P	FBGN0000594
drosophila_melanogaster	Glt	FBGN0001114
drosophila_melanogaster	Jhe	FBGN0010052
drosophila_melanogaster	alpha-Est1	FBGN0015568
drosophila_melanogaster	alpha-Est10	FBGN0015569
drosophila_melanogaster	alpha-Est2	FBGN0015570
drosophila_melanogaster	alpha-Est3	FBGN0015571
drosophila_melanogaster	alpha-Est4	FBGN0015572
drosophila_melanogaster	alpha-Est6	FBGN0015574
drosophila_melanogaster	alpha-Est7	FBGN0015575
drosophila_melanogaster	alpha-Est8	FBGN0015576
drosophila_melanogaster	alpha-Est9	FBGN0015577
drosophila_melanogaster	CG4757	FBGN0027584
drosophila_melanogaster	CG9287	FBGN0032057
drosophila_melanogaster	CG9289	FBGN0032058
drosophila_melanogaster	CG3841	FBGN0032131
drosophila_melanogaster	CG4382	FBGN0032132
drosophila_melanogaster	Jhedup	FBGN0034076
drosophila_melanogaster	gas	FBGN0034736
drosophila_melanogaster	alpha-Est5	FBGN0261393
caenorhabditis_elegans		WBGENE00000037
caenorhabditis_elegans		WBGENE00000038
caenorhabditis_elegans		WBGENE00007691
caenorhabditis_elegans		WBGENE00007692
caenorhabditis_elegans		WBGENE00007693
caenorhabditis_elegans		WBGENE00007695
caenorhabditis_elegans		WBGENE00008451
caenorhabditis_elegans		WBGENE00011362
caenorhabditis_elegans		WBGENE00011364
caenorhabditis_elegans		WBGENE00013873
caenorhabditis_elegans		WBGENE00013874
caenorhabditis_elegans		WBGENE00013875
caenorhabditis_elegans		WBGENE00015067
caenorhabditis_elegans		WBGENE00015071
caenorhabditis_elegans		WBGENE00015279
caenorhabditis_elegans		WBGENE00015284
caenorhabditis_elegans		WBGENE00016595
caenorhabditis_elegans		WBGENE00016862
caenorhabditis_elegans		WBGENE00016863
caenorhabditis_elegans	cest-27	WBGENE00018958
caenorhabditis_elegans		WBGENE00020688

Paralogs (13): TG (ENSG00000042832), ACHE (ENSG00000087085), BCHE (ENSG00000114200), NLGN4X (ENSG00000146938), CES5A (ENSG00000159398), NLGN4Y (ENSG00000165246), NLGN2 (ENSG00000169992), CEL (ENSG00000170835), CES4A (ENSG00000172824), CES3 (ENSG00000172828), CES2 (ENSG00000172831), NLGN3 (ENSG00000196338), CES1 (ENSG00000198848)

Protein

Protein identifiers

Neuroligin-1 — Q8N2Q7 (reviewed: Q8N2Q7)

All UniProt accessions (5): A0A1D5RMP7, A0A8Q3SHM6, C9J4D3, C9JWG7, Q8N2Q7

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members. Plays a role in synapse function and synaptic signal transmission, and probably mediates its effects by recruiting and clustering other synaptic proteins. May promote the initial formation of synapses, but is not essential for this. In vitro, triggers the de novo formation of presynaptic structures. May be involved in specification of excitatory synapses. Required to maintain wakefulness quality and normal synchrony of cerebral cortex activity during wakefulness and sleep. The protein is involved in nervous system development.

Subunit / interactions. Interacts with neurexins NRXN1, NRXN2 and NRXN3. Interaction with neurexins is mediated by heparan sulfate glycan modification on neurexin. Interacts with NLGN3. Interacts with AIP1 and PDZRN3. Interacts (via its C-terminus) with DLG4/PSD-95 (via PDZ domain 3). Interacts with GOPC.

Subcellular location. Cell membrane. Postsynaptic density. Synaptic cleft. Synaptic cell membrane. Cell projection. Dendrite. Synapse.

Tissue specificity. Expressed in the blood vessel walls (at protein level). Highly expressed in brain through prenatal stages, and at lower levels in pancreas islet beta cells.

Post-translational modifications. N-glycosylated, contains high-mannose, hybrid, complex and sialylated N-glycans. N-glycosylation is essential for localization to synapses, dendrites, and the cell membrane, and enhances its availability for trans-synaptic adhesion. O-glycosylated.

Disease relevance. Autism 20 (AUTS20) [MIM:618830] A complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate intellectual disability. The transmission pattern of AUTS20 is consistent with autosomal dominant inheritance. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the type-B carboxylesterase/lipase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N2Q7-3	1	yes
Q8N2Q7-2	2

RefSeq proteins (15): NP_001352852, NP_001352853, NP_001352854, NP_001352855, NP_001352856, NP_001352857, NP_001352858, NP_001352859, NP_001352860, NP_001352861, NP_001352862, NP_001352863, NP_001352864, NP_001352865, NP_055747 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000460	Nlgn	Family
IPR002018	CarbesteraseB	Domain
IPR019819	Carboxylesterase_B_CS	Conserved_site
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR051093	Neuroligin/BSAL	Family

Pfam: PF00135

UniProt features (87 total): strand 26, helix 25, sequence variant 7, turn 7, glycosylation site 6, compositionally biased region 3, disulfide bond 3, region of interest 3, topological domain 2, signal peptide 1, chain 1, splice variant 1, sequence conflict 1, transmembrane region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5OJK	X-RAY DIFFRACTION	2.55
5OJ6	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N2Q7-F1	77.23	0.60

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 (3): 117–153, 362–373, 532–566

Glycosylation sites (6): 109, 323, 363, 567, 703, 706

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6794361	Neurexins and neuroligins

MSigDB gene sets: 404 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_DENDRITE_DEVELOPMENT, GOBP_SYNAPTIC_VESICLE_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_NEGATIVE_REGULATION_OF_DENDRITIC_SPINE_DEVELOPMENT, GOBP_HETEROPHILIC_CELL_CELL_ADHESION, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_BEHAVIOR, GOBP_VESICLE_LOCALIZATION, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_SYNAPSE_ASSEMBLY, GOBP_MEMBRANE_BIOGENESIS, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GOBP_DENDRITIC_SPINE_DEVELOPMENT

GO Biological Process (51): protein targeting (GO:0006605), heterophilic cell-cell adhesion (GO:0007157), neuron cell-cell adhesion (GO:0007158), nervous system development (GO:0007399), synapse assembly (GO:0007416), positive regulation of circadian sleep/wake cycle, wakefulness (GO:0010841), obsolete synaptic vesicle targeting (GO:0016080), calcium-dependent cell-cell adhesion (GO:0016339), neuronal signal transduction (GO:0023041), neuron projection development (GO:0031175), positive regulation of synaptic transmission, GABAergic (GO:0032230), protein localization to synapse (GO:0035418), establishment of protein localization (GO:0045184), regulation of neuron differentiation (GO:0045664), rhythmic process (GO:0048511), cytoskeletal matrix organization at active zone (GO:0048789), neuron projection morphogenesis (GO:0048812), modulation of chemical synaptic transmission (GO:0050804), positive regulation of filopodium assembly (GO:0051491), positive regulation of synapse assembly (GO:0051965), positive regulation of synaptic transmission, glutamatergic (GO:0051968), positive regulation of dendritic spine development (GO:0060999), negative regulation of dendritic spine morphogenesis (GO:0061002), cellular response to calcium ion (GO:0071277), terminal button organization (GO:0072553), synaptic vesicle clustering (GO:0097091), postsynaptic membrane assembly (GO:0097104), presynaptic membrane assembly (GO:0097105), AMPA glutamate receptor clustering (GO:0097113), NMDA glutamate receptor clustering (GO:0097114), neurexin clustering involved in presynaptic membrane assembly (GO:0097115), postsynaptic density protein 95 clustering (GO:0097119), receptor localization to synapse (GO:0097120), NMDA selective glutamate receptor signaling pathway (GO:0098989), AMPA selective glutamate receptor signaling pathway (GO:0098990), presynapse assembly (GO:0099054), neuron projection arborization (GO:0140058), positive regulation of ruffle assembly (GO:1900029), positive regulation of neuromuscular synaptic transmission (GO:1900075), positive regulation of synaptic vesicle endocytosis (GO:1900244)

GO Molecular Function (8): amyloid-beta binding (GO:0001540), PDZ domain binding (GO:0030165), signaling receptor activity (GO:0038023), neurexin family protein binding (GO:0042043), identical protein binding (GO:0042802), cell adhesion molecule binding (GO:0050839), scaffold protein binding (GO:0097110), cell adhesion mediator activity (GO:0098631)

GO Cellular Component (25): Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), cell surface (GO:0009986), postsynaptic density (GO:0014069), membrane (GO:0016020), dendrite (GO:0030425), neuromuscular junction (GO:0031594), filopodium tip (GO:0032433), synaptic cleft (GO:0043083), dendritic spine (GO:0043197), signaling receptor complex (GO:0043235), synapse (GO:0045202), postsynaptic membrane (GO:0045211), excitatory synapse (GO:0060076), protein complex involved in cell-cell adhesion (GO:0098635), presynapse (GO:0098793), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), asymmetric, glutamatergic, excitatory synapse (GO:0098985), postsynaptic specialization membrane (GO:0099634), extracellular region (GO:0005576), external side of plasma membrane (GO:0009897), synaptic membrane (GO:0097060), neuron to neuron synapse (GO:0098984)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein-protein interactions at synapses	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
synapse	6
cell-cell adhesion	3
protein binding	3
asymmetric synapse	2
postsynapse	2
establishment of protein localization	1
system development	1
nervous system development	1
cell junction assembly	1
synapse organization	1
regulation of circadian sleep/wake cycle, wakefulness	1
circadian sleep/wake cycle, wakefulness	1
positive regulation of circadian rhythm	1
positive regulation of behavior	1
signal transduction	1
neuron development	1
plasma membrane bounded cell projection organization	1
regulation of synaptic transmission, GABAergic	1
positive regulation of synaptic transmission	1
synaptic transmission, GABAergic	1
protein localization to cell junction	1
establishment of localization	1
neuron differentiation	1
regulation of cell differentiation	1
biological_process	1
cortical cytoskeleton organization	1
neuron projection development	1
plasma membrane bounded cell projection morphogenesis	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
filopodium assembly	1
regulation of filopodium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
synapse assembly	1
positive regulation of nervous system development	1
regulation of synapse assembly	1
positive regulation of cell junction assembly	1
peptide binding	1
protein domain specific binding	1

Protein interactions and networks

STRING

1920 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NLGN1	NRXN2	Q9P2S2	999
NLGN1	NRXN1	Q9ULB1	999
NLGN1	DLG4	P78352	996
NLGN1	SHANK3	Q9BYB0	955
NLGN1	NXN	Q6DKJ4	949
NLGN1	MAGI2	Q86UL8	877
NLGN1	DLGAP1	P78335	843
NLGN1	SHANK1	Q9Y566	837
NLGN1	CNTN4	Q8IWV2	836
NLGN1	SHANK2	Q9UPX8	831
NLGN1	NRXN3	Q9Y4C0	826
NLGN1	LRRTM2	O43300	806
NLGN1	CADM1	Q9BY67	794
NLGN1	NPTX2	P47972	788
NLGN1	CNTNAP2	Q9UHC6	741

IntAct

19 interactions, top by confidence:

A	B	Type	Score
ABI2	CYFIP1	psi-mi:“MI:0915”(physical association)	0.870
ADCY9	NEMP1	psi-mi:“MI:0914”(association)	0.640
BRK1	CYFIP1	psi-mi:“MI:0914”(association)	0.640
	NLGN1	psi-mi:“MI:0407”(direct interaction)	0.440
Dlg3	NLGN1	psi-mi:“MI:0407”(direct interaction)	0.440
DLG4	NLGN1	psi-mi:“MI:0407”(direct interaction)	0.440
TRADD	HNRNPCL2	psi-mi:“MI:0914”(association)	0.350
ARID1B	RTCA	psi-mi:“MI:0914”(association)	0.350
TLK2	IGKV1D-13	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
TNFSF18	TMEM120B	psi-mi:“MI:0914”(association)	0.350
NLGN3	TMEM131L	psi-mi:“MI:0914”(association)	0.350
LLCFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
GPIHBP1	SAC3D1	psi-mi:“MI:0914”(association)	0.350
EDDM3A	PLXNA2	psi-mi:“MI:0914”(association)	0.350
SEMA4B	NLGN1	psi-mi:“MI:0914”(association)	0.350
ADCY9	COX7A2L	psi-mi:“MI:0914”(association)	0.350
CD247	RSL1D1	psi-mi:“MI:0914”(association)	0.350

BioGRID (29): NLGN1 (Affinity Capture-MS), NLGN1 (Affinity Capture-MS), NLGN1 (Reconstituted Complex), NLGN1 (Affinity Capture-MS), NLGN1 (Reconstituted Complex), NLGN1 (Reconstituted Complex), DLG4 (Two-hybrid), DLG3 (Two-hybrid), DLG2 (Two-hybrid), NLGN1 (Reconstituted Complex), NLGN1 (Reconstituted Complex), NLGN1 (Reconstituted Complex), NLGN1 (Reconstituted Complex), NLGN1 (PCA), NLGN1 (Proximity Label-MS)

ESM2 similar proteins: A0A8M2B818, A0A8M9PFP2, A1XQX3, A1XQY0, A1XQY3, B0S5G3, D0PRN4, F1N4M2, L7VG99, O35158, O35464, O61307, Q01083, Q14DG7, Q24322, Q3KN41, Q3UHK6, Q3UN70, Q568T5, Q58EG3, Q5R7F5, Q62765, Q62889, Q66IV1, Q76KF0, Q7T2X6, Q8BMA3, Q8N2Q7, Q8NFY4, Q8VDA1, Q90Z04, Q91713, Q96LU7, Q9DER5, Q9ER65, Q9H2E6, Q9H4D0, Q9HDB5, Q9NT68, Q9NZ94

Diamond homologs: A0A0E4AET8, A0A0G3FWY4, B0F2B4, D4ASH1, G3V7J5, I6Y9F7, O00748, O08710, O16168, O16173, O46421, P06882, P0C6R3, P10959, P12337, P16303, P16854, P17573, P19835, P22394, P23141, P23953, P24484, P25726, P25727, P35501, P35502, P37967, P71668, P79066, P86325, P96402, P9WK86, P9WK87, Q01470, Q07085, Q1PET6, Q29550, Q47M62, Q50681

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
NLGN1	“up-regulates activity”	NRXN1	binding
NLGN1	“up-regulates activity”	NRXN2	binding
NLGN1	“up-regulates activity”	NRXN3	binding
NLGN1	“up-regulates activity”	DLG4	relocalization
RORA	“up-regulates quantity by expression”	NLGN1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	104
Likely benign	20
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

6657 predictions. Top by Δscore:

Variant	Effect	Δscore
3:173415386:A:G	acceptor_gain	1.0000
3:173807676:CCAG:C	acceptor_loss	1.0000
3:173807677:CAGAT:C	acceptor_loss	1.0000
3:173807678:AGA:A	acceptor_loss	1.0000
3:173807833:G:GG	donor_gain	1.0000
3:173807833:GTAA:G	donor_loss	1.0000
3:173807834:T:A	donor_loss	1.0000
3:173398483:GCCTT:G	donor_gain	0.9900
3:173398488:G:GG	donor_gain	0.9900
3:173415385:A:AG	acceptor_gain	0.9900
3:173415387:G:GG	acceptor_gain	0.9900
3:173416394:T:A	acceptor_gain	0.9900
3:173416481:GT:G	donor_gain	0.9900
3:173434991:T:A	acceptor_gain	0.9900
3:173471130:G:GT	donor_gain	0.9900
3:173536151:T:TA	acceptor_gain	0.9900
3:173576892:T:TA	acceptor_gain	0.9900
3:173577020:T:G	donor_gain	0.9900
3:173733456:GTA:G	acceptor_gain	0.9900
3:173733610:G:GT	donor_gain	0.9900
3:173805748:T:G	donor_gain	0.9900
3:173807678:A:AG	acceptor_gain	0.9900
3:173807679:G:GG	acceptor_gain	0.9900
3:173807679:GA:G	acceptor_gain	0.9900
3:173807679:GAT:G	acceptor_gain	0.9900
3:173807679:GATA:G	acceptor_gain	0.9900
3:173888589:G:GG	donor_gain	0.9900
3:173936820:GGCA:G	donor_gain	0.9900
3:173936821:GCA:G	donor_gain	0.9900
3:173936821:GCAG:G	donor_gain	0.9900

AlphaMissense

5535 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000000489 (3:174019654 G>C), RS1000000856 (3:173610543 G>A,T), RS1000002251 (3:173671312 C>A), RS1000007924 (3:173443118 A>G,T), RS1000008883 (3:173853658 C>G,T), RS1000009231 (3:173938398 A>T), RS1000010188 (3:174064606 G>A), RS1000012532 (3:173535909 C>A,T), RS1000016441 (3:173422700 T>A), RS1000021258 (3:173652298 T>C), RS1000026118 (3:174192918 G>C,T), RS1000031566 (3:174278585 A>G), RS1000031827 (3:174107907 C>G,T), RS1000031961 (3:173864152 T>G), RS1000037403 (3:174170442 C>T)

Disease associations

OMIM: gene MIM:600568 | disease phenotypes: MIM:189800, MIM:618830, MIM:300958

GenCC curated gene-disease

Disease	Classification	Inheritance
autism, susceptibility to, 20	Moderate	Autosomal dominant
autism, susceptiblity to	Limited	Autosomal recessive

Mondo (5): preeclampsia (MONDO:0005081), autism, susceptibility to, 20 (MONDO:0030004), primary ovarian failure (MONDO:0005387), intellectual disability, X-linked 102 (MONDO:0010497), autism, susceptiblity to (MONDO:0020836)

Orphanet (3): Preeclampsia (Orphanet:275555), X-linked intellectual disability-hypotonia-movement disorder syndrome (Orphanet:457260), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000722	Compulsive behaviors
HP:0000729	Autistic behavior
HP:0001263	Global developmental delay
HP:0007018	Attention deficit hyperactivity disorder
HP:0012760	Reduced social responsiveness

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000689_1	Major depressive disorder	9.000000e-06
GCST002129_5	Periodontitis (DPAL)	6.000000e-06
GCST002759_13	Motion sickness	6.000000e-13
GCST004001_3	Bipolar disorder or attention deficit hyperactivity disorder	1.000000e-07
GCST004765_22	Total cholesterol change in response to fenofibrate in statin-treated type 2 diabetes	1.000000e-06
GCST005830_79	Hand grip strength	7.000000e-09
GCST007324_164	Adventurousness	1.000000e-11
GCST008152_132	Weight	5.000000e-06
GCST008159_38	Waist-to-hip ratio adjusted for BMI	8.000000e-06
GCST009028_35	Adverse response to drug	3.000000e-07
GCST009391_1546	Metabolite levels	5.000000e-06
GCST010173_64	Triglyceride levels	2.000000e-15
GCST010988_124	Adult body size	6.000000e-14
GCST011742_45	Triglyceride levels in HIV infection	3.000000e-06
GCST90020053_4	Frailty index	2.000000e-09

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0006928	motion sickness
EFO:0007806	total cholesterol change measurement
EFO:0006941	grip strength measurement
EFO:0008579	risk-taking behaviour
EFO:0004338	body weight
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0009658	adverse effect
EFO:0010511	niacinamide measurement
EFO:0004530	triglyceride measurement
EFO:0009885	frailty measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D011225	Pre-Eclampsia	C12.050.703.395.249
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs16857540	NLGN1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	6
Benzo(a)pyrene	decreases expression, decreases methylation, increases mutagenesis, affects methylation	4
trichostatin A	decreases expression, affects cotreatment	3
entinostat	decreases expression, affects cotreatment	2
Arsenic Trioxide	decreases expression, increases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, decreases methylation	1
sotorasib	affects cotreatment, decreases expression	1
methyleugenol	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases methylation	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, increases methylation	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation, increases methylation	1
Arsenic	affects methylation	1
Catechin	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00117546	PHASE4	UNKNOWN	Cardiovascular and Autonomic Reactivity in Women With a History of Pre-eclampsia
NCT00567957	PHASE4	UNKNOWN	Remifentanil for General Anesthesia in Preeclamptics
NCT01030627	PHASE4	COMPLETED	Treatment Approaches to Preeclampsia
NCT01352234	PHASE4	COMPLETED	Comparison of Doses of Acetylsalicylic Acid in Women With Previous History of Preeclampsia
NCT01361425	PHASE4	UNKNOWN	Anti-Hypertensive Treatment In Stable Pregnant Women With Severe Pre-Eclampsia (Metildopape)
NCT01729468	PHASE4	COMPLETED	Prevention of Pre-eclampsia and SGA by Low-Dose Aspirin in Nulliparous Women With Abnormal First-trimester Uterine Artery Dopplers
NCT01761916	PHASE4	COMPLETED	Clonidine Versus Captopril for Treatment of Postpartum Very High Blood Pressure
NCT01912677	PHASE4	COMPLETED	Oral Antihypertensive Regimens for Management of Hypertension in Pregnancy
NCT02025426	PHASE4	TERMINATED	Phenylephrine Versus Ephedrine in Pre-eclampsia
NCT02091401	PHASE4	COMPLETED	A Trial Comparing Treatment With the Springfusor Infusion Pump to the IV Magnesium Sulfate Regimen
NCT02163655	PHASE4	COMPLETED	Diuretics for Postpartum High Blood Pressure in Preeclampsia
NCT02338687	PHASE4	COMPLETED	Low Dose Calcium to Prevent Preeclampsia
NCT02396030	PHASE4	TERMINATED	Different Schemes of Magnesium Sulfate for Preeclampsia
NCT02531490	PHASE4	UNKNOWN	Early Vascular Adjustments During Hypertensive Pregnancy
NCT02699827	PHASE4	COMPLETED	Adding MgSO4 to Epidural Levobupivacaine in CS for Patients With Preeclampsia
NCT02835339	PHASE4	COMPLETED	Magnesium Sulfate in Obese Preeclamptics
NCT02891174	PHASE4	COMPLETED	The Effect of Ibuprofen on Post-partum Blood Pressure in Women With Hypertensive Disorders of Pregnancy
NCT02911701	PHASE4	COMPLETED	Effect of Acetaminophen on Postpartum Blood Pressure Control in Preeclampsia With Severe Features
NCT03171480	PHASE4	COMPLETED	Use of Nitrous Oxide Donor for Labor Induction in Women With PreEclampsia
NCT03233880	PHASE4	UNKNOWN	Impact of Antichlamydial Treatment on the Rate of Preeclampsia
NCT03237000	PHASE4	UNKNOWN	Effect of Administering Intravenous Magnesium Sulfate on Fetal Cardiotocography and Neonatal Outcome in Preeclamptic Patients
NCT03506724	PHASE4	COMPLETED	Response to Anti-hypertensives in Pregnant and Postpartum Patients
NCT03674606	PHASE4	COMPLETED	Trial of Early Screening Test for Pre-eclampsia and Growth Restriction
NCT03735433	PHASE4	TERMINATED	The Effect of Two Aspirin Dosing Strategies for Obese Women at High Risk for Preeclampsia
NCT03824119	PHASE4	UNKNOWN	Postpartum NSAIDS and Maternal Hypertension
NCT04051567	PHASE4	UNKNOWN	Low-dose Aspirin for Prevention of Adverse Pregnancy Outcomes in Twin Pregnancies
NCT04077853	PHASE4	COMPLETED	Progesterone in Expectantly Managed Early-onset Preeclampsia
NCT04158830	PHASE4	WITHDRAWN	Aspirin (ASA) Therapy and Preeclampsia Prevention
NCT04424693	PHASE4	UNKNOWN	Comparing the Incidence of Preeclampsia Between Pregnant Women Receiving Tdap Vaccinations at Week 28 or at Week 36
NCT04631627	PHASE4	UNKNOWN	Early Prediction and Randomised Prevention of Preeclampsia With Low Dose Aspirin in Chinese Cohort
NCT04656665	PHASE4	UNKNOWN	The Effectiveness of Aspirin on Preventing Pre-eclampsia
NCT04797949	PHASE4	WITHDRAWN	Adherence to Universal Aspirin Compared to Screening Indicated Aspirin for Prevention of Preeclampsia
NCT04908982	PHASE4	UNKNOWN	Aspirin for the Prevention of Preeclampsia in Women With Stage 1 Hypertension
NCT05221164	PHASE4	UNKNOWN	162 mg of Aspirin for Prevention of Preeclampsia
NCT05294952	PHASE4	UNKNOWN	co Ihibtory Receptor in Preeclampsia
NCT05514847	PHASE4	ACTIVE_NOT_RECRUITING	Low Dose Aspirin for Preterm Preeclampsia Preventionmg/day Dose in High-risk Patients
NCT05586373	PHASE4	COMPLETED	Ibuprofen vs Dipyrone After C-section in Preeclampsia
NCT06069102	PHASE4	COMPLETED	Optimal Blood Pressure Treatment Thresholds Postpartum
NCT06107335	PHASE4	NOT_YET_RECRUITING	Effect of Albumin Versus Routine Care on Hemodynamic Response and Stability in Patients With Preeclampsia Guided by a Non-invasive Hemodynamic Monitoring System During Cesarean Delivery With Spinal Anesthesia
NCT06281665	PHASE4	RECRUITING	Treatment With Aspirin After Preeclampsia: TAP Trial