NLGN4Y

Summary

NLGN4Y (neuroligin 4 Y-linked, HGNC:15529) is a protein-coding gene on chromosome Yq11.221, encoding Neuroligin-4, Y-linked (Q8NFZ3). Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.

This gene encodes a type I membrane protein that belongs to the family of neuroligins, which are cell adhesion molecules present at the postsynaptic side of the synapse, and may be essential for the formation of functional synapses. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 22829 — RefSeq curated summary.

At a glance

• Gene–disease (curated): male infertility with azoospermia or oligozoospermia due to single gene mutation (Limited, GenCC)
• Clinical variants (ClinVar): 48 total
• MANE Select transcript: NM_001365588

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15529
Approved symbol	NLGN4Y
Name	neuroligin 4 Y-linked
Location	Yq11.221
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0951
Ensembl gene	ENSG00000165246
Ensembl biotype	protein_coding
OMIM	400028
Entrez	22829

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 29 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000339174, ENST00000355905, ENST00000382868, ENST00000382872, ENST00000413217, ENST00000471252, ENST00000476359, ENST00000481089, ENST00000643089, ENST00000645399, ENST00000684976, ENST00000877962, ENST00000877963, ENST00000877964, ENST00000877965, ENST00000877966, ENST00000926508, ENST00000926509, ENST00000926510, ENST00000926511, ENST00000926512, ENST00000926513, ENST00000926514, ENST00000926515, ENST00000926516, ENST00000926517, ENST00000926518, ENST00000926519, ENST00000926520, ENST00000926521, ENST00000926522, ENST00000926523

RefSeq mRNA: 12 — MANE Select: NM_001365588 NM_001164238, NM_001206850, NM_001365584, NM_001365586, NM_001365588, NM_001365590, NM_001365591, NM_001365592, NM_001365593, NM_001394830, NM_001394831, NM_014893

CCDS: CCDS14788, CCDS56619, CCDS94714

Canonical transcript exons

ENST00000684976 — 7 exons

Exon	Start	End
ENSE00001390456	14622009	14622591
ENSE00001955812	14524529	14524708
ENSE00003537524	14824188	14824373
ENSE00003554354	14719459	14719518
ENSE00003686712	14829730	14830519
ENSE00003691073	14723117	14723269
ENSE00003928154	14840413	14845654

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 82.09.

FANTOM5 (CAGE): breadth broad, TPM avg 4.2475 / max 159.4089, expressed in 726 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
201178	1.9463	360
201179	1.4849	656
201181	0.3194	206
201180	0.2803	164
201182	0.2165	123

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.09	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.71	gold quality
prefrontal cortex	UBERON:0000451	74.72	gold quality
endothelial cell	CL:0000115	74.51	gold quality
Brodmann (1909) area 9	UBERON:0013540	73.34	gold quality
ventricular zone	UBERON:0003053	73.30	gold quality
corpus callosum	UBERON:0002336	72.97	gold quality
ganglionic eminence	UBERON:0004023	72.39	gold quality
choroid plexus epithelium	UBERON:0003911	72.21	silver quality
Brodmann (1909) area 23	UBERON:0013554	71.97	gold quality
prostate gland	UBERON:0002367	70.37	gold quality
cortical plate	UBERON:0005343	67.99	gold quality
frontal cortex	UBERON:0001870	67.59	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	67.36	gold quality
neocortex	UBERON:0001950	66.97	gold quality
rectum	UBERON:0001052	66.78	gold quality
parietal pleura	UBERON:0002400	66.12	gold quality
cerebral cortex	UBERON:0000956	65.93	gold quality
primary visual cortex	UBERON:0002436	65.82	gold quality
cerebellar vermis	UBERON:0004720	65.18	gold quality
middle temporal gyrus	UBERON:0002771	64.85	silver quality
telencephalon	UBERON:0001893	64.75	gold quality
metanephros cortex	UBERON:0010533	64.52	gold quality
entorhinal cortex	UBERON:0002728	64.46	gold quality
pleura	UBERON:0000977	64.41	gold quality
cingulate cortex	UBERON:0003027	64.25	gold quality
right hemisphere of cerebellum	UBERON:0014890	64.20	gold quality
cauda epididymis	UBERON:0004360	64.19	gold quality
nucleus accumbens	UBERON:0001882	64.10	gold quality
islet of Langerhans	UBERON:0000006	64.05	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.56
E-MTAB-4850	no	0.38

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

147 targeting NLGN4Y, 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-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-627-3P	99.90	71.42	3316

Literature-anchored findings (GeneRIF, showing 7)

• 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)
• The coding sequences and splice junctions of the NLGN4Y gene were analyzed in 335 male samples (290 with autism and 45 with mental retardation) to analyze sequence variants in NLGN4Y that are associated with autism or mental retardation. (PMID:18628683)
• investigated 12 single-nucleotide polymorphisms in Y-linked neuroligin 4, transducin b-like 1, and eukaryotic translation initiation factor 1a genes, results suggest a Y chromosome effect in autism (PMID:19605777)
• Expression of NLGN4Y, a gene that may be involved in synaptic function, is increased in boys with XYY (PMID:25558953)
• Results suggest that NLGN4Y is an important negative regulator in prostate cancer progression. (PMID:27626693)
• Results suggest an association between a maternal immune response to neuroligin 4 Y-linked (NLGN4Y) and subsequent sexual orientation in male offspring. (PMID:29229842)
• A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y. (PMID:32243781)

Cross-species orthologs

45 orthologs

Organism	Symbol	Gene ID
danio_rerio	nlgn4xb	ENSDARG00000077761
danio_rerio	nlgn4xa	ENSDARG00000079455
mus_musculus	Nlgn4l	ENSMUSG00000121607
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), NLGN1 (ENSG00000169760), NLGN2 (ENSG00000169992), CEL (ENSG00000170835), CES4A (ENSG00000172824), CES3 (ENSG00000172828), CES2 (ENSG00000172831), NLGN3 (ENSG00000196338), CES1 (ENSG00000198848)

Protein

Protein identifiers

Neuroligin-4, Y-linked — Q8NFZ3 (reviewed: Q8NFZ3)

All UniProt accessions (5): A0A2R8YDT7, A6NMU8, B4DHI3, Q8NFZ3, H0Y7G6

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.

Subunit / interactions. Homodimer. Interacts with NRXN1 in a calcium-dependent manner. Interaction with neurexins is mediated by heparan sulfate glycan modification on neurexin. Interacts through its C-terminus with DLG4/PSD-95 third PDZ domain.

Subcellular location. Cell membrane. Postsynaptic density membrane. Cell projection. Dendritic spine. Dendrite. Synapse.

Tissue specificity. Expressed in fetal and adult brain, prostate and testis.

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.

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

Isoforms (4)

UniProt ID	Names	Canonical?
Q8NFZ3-1	1	yes
Q8NFZ3-2	2
Q8NFZ3-3	3
Q8NFZ3-4	4

RefSeq proteins (12): NP_001157710, NP_001193779, NP_001352513, NP_001352515, NP_001352517, NP_001352519, NP_001352520, NP_001352521, NP_001352522, NP_001381759, NP_001381760, NP_055708 (=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 (20 total): splice variant 5, disulfide bond 3, glycosylation site 2, topological domain 2, region of interest 2, signal peptide 1, chain 1, sequence conflict 1, transmembrane region 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NFZ3-F1	79.06	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.

Post-translational modifications (1): 712

Disulfide bonds (3): 110–146, 306–317, 476–510

Glycosylation sites (2): 511, 102

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6794361	Neurexins and neuroligins

MSigDB gene sets: 90 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_SYNAPSE_ASSEMBLY, GOBP_CELL_CELL_ADHESION, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_LEARNING, GOBP_BIOLOGICAL_PROCESS_INVOLVED_IN_INTRASPECIES_INTERACTION_BETWEEN_ORGANISMS, BROWNE_HCMV_INFECTION_14HR_DN, GOBP_VOCALIZATION_BEHAVIOR, GOBP_NEURON_CELL_CELL_ADHESION, MORF_RAB3A, GOBP_CELL_JUNCTION_ASSEMBLY, GOCC_NEURON_PROJECTION, GOMF_SIGNALING_RECEPTOR_BINDING

GO Biological Process (7): neuron cell-cell adhesion (GO:0007158), synapse assembly (GO:0007416), learning (GO:0007612), social behavior (GO:0035176), vocalization behavior (GO:0071625), presynapse assembly (GO:0099054), cell adhesion (GO:0007155)

GO Molecular Function (5): neurexin family protein binding (GO:0042043), cell adhesion molecule binding (GO:0050839), scaffold protein binding (GO:0097110), cell adhesion mediator activity (GO:0098631), protein binding (GO:0005515)

GO Cellular Component (10): plasma membrane (GO:0005886), membrane (GO:0016020), dendrite (GO:0030425), synapse (GO:0045202), postsynaptic density membrane (GO:0098839), symmetric, GABA-ergic, inhibitory synapse (GO:0098983), asymmetric, glutamatergic, excitatory synapse (GO:0098985), postsynaptic specialization membrane (GO:0099634), postsynaptic membrane (GO:0045211), 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
behavior	2
protein binding	2
postsynaptic membrane	2
synaptic membrane	2
cell-cell adhesion	1
nervous system development	1
cell junction assembly	1
synapse organization	1
learning or memory	1
biological process involved in intraspecies interaction between organisms	1
synapse assembly	1
cellular component assembly	1
presynapse organization	1
cellular process	1
signaling receptor binding	1
cell adhesion	1
cell adhesion molecule binding	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1
neuron projection	1
dendritic tree	1
cell junction	1
postsynaptic density	1
postsynaptic specialization membrane	1
symmetric synapse	1
inhibitory synapse	1
GABA-ergic synapse	1
asymmetric synapse	1
excitatory synapse	1
glutamatergic synapse	1
postsynaptic specialization	1
postsynapse	1
synapse	1

Protein interactions and networks

STRING

968 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NLGN4Y	NRXN2	Q9P2S2	998
NLGN4Y	NRXN1	Q9ULB1	998
NLGN4Y	DLG4	P78352	972
NLGN4Y	SHANK3	Q9BYB0	796
NLGN4Y	ZFY	P08048	752
NLGN4Y	EIF1AY	O14602	745
NLGN4Y	USP9Y	O00507	734
NLGN4Y	DDX3Y	O15523	723
NLGN4Y	MAGI2	Q86UL8	718
NLGN4Y	SHANK2	Q9UPX8	710
NLGN4Y	CADM1	Q9BY67	689
NLGN4Y	DLG3	Q92796	687
NLGN4Y	DLGAP1	P78335	670
NLGN4Y	KDM5D	Q9BY66	669
NLGN4Y	NXN	Q6DKJ4	649

IntAct

6 interactions, top by confidence:

A	B	Type	Score
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
NLGN3	TMEM131L	psi-mi:“MI:0914”(association)	0.350
NLGN4Y	UBB	psi-mi:“MI:0914”(association)	0.350
NLGN4Y	PRIM1	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): NLGN4Y (Affinity Capture-MS), PRIM1 (Affinity Capture-MS), PRIM2 (Affinity Capture-MS), NLGN4Y (Affinity Capture-RNA), PRIM1 (Affinity Capture-MS), PRIM2 (Affinity Capture-MS), NLGN4Y (Affinity Capture-MS), UBB (Affinity Capture-MS), NLGN4Y (Affinity Capture-RNA)

ESM2 similar proteins: A5D7U4, F1MJW3, H1AFJ5, H1AFJ6, H1AFJ7, H2LRU7, H2QAR5, H2QAR6, H9GBX2, K7FQW8, K7FSQ4, K7GET2, O13262, O13263, O35240, O62816, O70397, O97742, P24585, P24612, P34886, P37090, P37091, P49653, P51167, P51168, P51169, P51170, P51171, P78348, Q17298, Q19038, Q28738, Q60NC0, Q62765, Q62889, Q6NXK8, Q6X1Y6, Q708S3, Q708S7

Diamond homologs: A0A060S684, A0A0E4AET8, A0A8B0RBM2, B0F2B4, D2D3B6, D6WMZ8, G3V7J5, I1RDA9, O00748, O16168, O16169, O16170, O16171, O16172, O16173, O42275, O46421, O62760, O62761, O70631, P04058, P06276, P07882, P08171, P0C6R3, P10959, P12337, P12992, P14943, P16303, P16854, P18142, P19835, P21837, P21927, P23141, P23953, P25725, P25726, P25727

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
NLGN4Y	“up-regulates activity”	NRXN1	binding
NLGN4Y	“up-regulates activity”	NRXN2	binding
NLGN4Y	“up-regulates activity”	NRXN3	binding
NLGN4Y	“up-regulates activity”	DLG4	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	7
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000032251 (Y:14756472 C>G), RS1000063290 (Y:14770959 T>C), RS1000146919 (Y:14546980 G>A), RS1000226611 (Y:14744173 T>C), RS1000235807 (Y:14559667 G>A), RS1000286539 (Y:14558626 T>C), RS1000376460 (Y:14715831 G>A), RS1000407485 (Y:14714582 T>G), RS1000468907 (Y:14530756 G>A,C), RS1000516623 (Y:14581114 G>T), RS1000627025 (Y:14562848 T>G), RS1000631650 (Y:14750464 C>T), RS1000707568 (Y:14723559 G>A), RS1000740101 (Y:14721800 A>C), RS1000757073 (Y:14540456 C>A)

Disease associations

OMIM: gene MIM:400028 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
male infertility with azoospermia or oligozoospermia due to single gene mutation	Limited	Y-linked inheritance

Mondo (1): (MONDO:0018393)

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

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

Chemical	Actions (top 5)	PubMed papers
Silicon Dioxide	increases expression, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
tobacco tar	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Diethylhexyl Phthalate	increases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
Aflatoxin B1	increases methylation	1
Copper Sulfate	decreases expression	1
Particulate Matter	increases expression	1

Clinical trials (associated diseases)

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