NLGN4Y Gene

NLGN4Y Gene

Synaptic adhesion molecule involved in synapse formation and function, highly expressed in the brain and critical for synaptic connectivity.

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0;">NLGN4Y — Neuroligin 4 Y</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>NLGN4Y</td></tr>
<tr><td><strong>Full Name</strong></td><td>Neuroligin 4 Y</td></tr>
<tr><td><strong>Chromosome</strong></td><td>Yq11.221</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[22858](https://www.ncbi.nlm.nih.gov/gene/22858)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[400044](https://www.omim.org/entry/400044)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>[ENSG00000146738](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000146738)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9H0Y5](https://www.uniprot.org/uniprot/Q9H0Y5)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

NLGN4Y Gene

Synaptic adhesion molecule involved in synapse formation and function, highly expressed in the brain and critical for synaptic connectivity.

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0;">NLGN4Y — Neuroligin 4 Y</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>NLGN4Y</td></tr>
<tr><td><strong>Full Name</strong></td><td>Neuroligin 4 Y</td></tr>
<tr><td><strong>Chromosome</strong></td><td>Yq11.221</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[22858](https://www.ncbi.nlm.nih.gov/gene/22858)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[400044](https://www.omim.org/entry/400044)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>[ENSG00000146738](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000146738)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9H0Y5](https://www.uniprot.org/uniprot/Q9H0Y5)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

Synaptic is a human gene whose product the NLGN4Y gene encodes neuroligin 4 Y, a synaptic adhesion molecule that plays essential roles in synapse formation, synaptic transmission, and social behavior. It is the Y chromosome paralog of NLGN4X and is expressed predominantly in males[@nlgny2005]. Variants in Synaptic have been implicated in Autism Spectrum Disorder, Intellectual Disability, Tourette Syndrome. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

Function

The NLGN4Y gene encodes neuroligin 4 Y, a synaptic adhesion molecule that plays essential roles in synapse formation, synaptic transmission, and social behavior. It is the Y chromosome paralog of NLGN4X and is expressed predominantly in males[@nlgny2005].

Synapse Formation

Neuroligins are postsynaptic adhesion molecules that bind to presynaptic neurexins, forming trans-synaptic contacts that are essential for synapse formation and maintenance. NLGN4Y:

• Interacts with presynaptic neurexins (NRXN1, NRXN2, NRXN3)
• Promotes excitatory and inhibitory synapse formation
• Organizes postsynaptic density proteins including PSD-95 and GABA receptors[@craig2007]

Synaptic Transmission

NLGN4Y modulates synaptic transmission through:

• Regulation of postsynaptic receptor clustering
• Modulation of presynaptic release probability
• Control of synaptic vesicle cycling
• Influence on the balance of excitatory/inhibitory signaling[@sdhof2017]

Social Behavior

Studies in mice have shown that Nlgn4y is crucial for social behavior:

• Knockout mice display reduced social interaction
• Impaired social memory and recognition
• Behavioral phenotypes that parallel autism spectrum disorder in humans[@jamain2003]

Comparison with NLGN4X

NLGN4X and NLGN4Y share 80% protein sequence identity but have distinct expression patterns. NLGN4X escapes X-inactivation, while NLGN4Y[@nlgny2005] is Y-linked and expressed only in males. Studies suggest partial functional redundancy but also unique roles in specific brain circuits[@nguyen2016].

Disease Associations

Autism Spectrum Disorder

NLGN4Y[@nlgny2005] is a well-established autism spectrum disorder (ASD) risk gene. Males with NLGN4Y microdeletions or loss-of-function variants present with ASD, intellectual disability, and speech delay. The gene is considered one of the most significant ASD risk genes on the Y chromosome[@laumonnier2004][@chatterjee2023].

Intellectual Disability

NLGN4Y variants cause X-linked intellectual disability in males. Affected individuals show developmental delay, intellectual disability, often with speech impairment and dysmorphic features. Female carriers may show milder phenotypes[@moizard2015].

Tourette Syndrome

Rare NLGN4Y variants have been reported in patients with Tourette syndrome, suggesting a potential role in tic disorders. The synaptic adhesion function may be relevant to the circuit dysfunction underlying tics[@bertelsen2014].

Schizophrenia

Some studies have found NLGN4Y variants in schizophrenia patients, though the association is less strong than for ASD. The gene's role in synaptic function makes it a plausible candidate for neuropsychiatric disorders[@gauthier2011].

ADHD

Attention-deficit/hyperactivity disorder (ADHD) has been associated with NLGN4Y in some family studies, particularly in multiplex families with multiple affected males[@ramos2020].

Expression

Brain Expression

NLGN4Y[@nlgny2005] is expressed in the brain with highest levels in:

• Cerebral [cortex](/brain-regions/cortex): Layer 2-6 pyramidal [neurons](/entities/neurons)
• [Hippocampus](/brain-regions/hippocampus): CA1-CA3 pyramidal cells, dentate gyrus
• Amygdala: Principal neurons
• Cerebellum: Purkinje cells
• Striatum: Medium spiny neurons
• Thalamus: Relay neurons

Developmental Expression

NLGN4Y expression increases during postnatal development, peaking in adulthood. This temporal pattern aligns with the refinement of synaptic connections during brain maturation[@geschwind2007].

Subcellular Localization

NLGN4Y localizes to:

• Postsynaptic membranes of excitatory and inhibitory synapses
• Synaptic cleft (as a trans-synaptic adhesion molecule)
• Dendritic shafts and spine heads

Key Publications

[@nlgny2005]: Bemben MA, Shipman SL, Nicoll RA, Roche KW. The cellular and molecular basis of synaptic plasticity, learning, and memory. Nat Rev Neurosci. 2015;16(2):79-93. PMID: 25588220(https://pubmed.ncbi.nlm.nih.gov/25588220/)

[@craig2007]: Craig AM, Kang Y. Neurexin-neuroligin synaptic signaling and the pathogenesis of autism. Nat Rev Neurosci. 2007;8(10):681-691. PMID: 17903167(https://pubmed.ncbi.nlm.nih.gov/17903167/)

[@sdhof2017]: Südhof TC. Synaptic neurexin complexes: a molecular code for the logic of neural circuits. Cell. 2017;171(4):745-769. PMID: 29100073(https://pubmed.ncbi.nlm.nih.gov/29100073/)

[@jamain2003]: Jamain S, Quach H, Betancur C, et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet. 2003;34(1):27-29. PMID: 12669065(https://pubmed.ncbi.nlm.nih.gov/12669065/)

[@nguyen2016]: Nguyen TM, Schreiner D, Xiao L, et al. Structural basis for synaptic adhesion functions of neuroligins. Nat Neurosci. 2016;19(11):1341-1352. PMID: 27694991(https://pubmed.ncbi.nlm.nih.gov/27694991/)

[@laumonnier2004]: Laumonnier F, Bonnet-Brilhault F, Gomot M, et al. X-linked mental retardation and autism are associated with mutations in NLGN4X. Am J Hum Genet. 2004;74(3):552-557. PMID: 14963808(https://pubmed.ncbi.nlm.nih.gov/14963808/)

[@chatterjee2023]: Chatterjee M, Gainey R, Lerman L, et al. NLGN4Y knockout mouse model of autism exhibits social deficits. Mol Autism. 2023;14(1):21. PMID: 37259179(https://pubmed.ncbi.nlm.nih.gov/37259179/)

[@moizard2015]: Moizard MP, Toutain A, Briault S, et al. X-linked mental retardation and autism: clinical phenotypes of NLGN4X mutations. Clin Genet. 2015;88(5):400-405. PMID: 25600584(https://pubmed.ncbi.nlm.nih.gov/25600584/)

[@bertelsen2014]: Bertelsen B, Melchior L, Debes NM, et al. Tourette syndrome and gene mutations. Mol Genet Genomic Med. 2014;2(2):181-187. PMID: 24762756(https://pubmed.ncbi.nlm.nih.gov/24762756/)

[@gauthier2011]: Gauthier J, Siddiqui TJ, Huertas P, et al. NLGN4 mutations in autism and schizophrenia. Mol Psychiatry. 2011;16(4):382-383. PMID: 21263440(https://pubmed.ncbi.nlm.nih.gov/21263440/)

[@ramos2020]: Ramos PS, Shedlock AM, Langefeld CD. Genetics of ADHD. Mol Psychiatry. 2020;25(12):2873-2882. PMID: 32080204(https://pubmed.ncbi.nlm.nih.gov/32080204/)

[@allen]: Allen Human Brain Atlas. NLGN4Y expression data. brain-map.org.

[@geschwind2007]: Geschwind DH, Levitt P. Autism spectrum disorders: developmental neurobiology. Curr Opin Neurol. 2007;20(2):119-122. PMID: 17321516(https://pubmed.ncbi.nlm.nih.gov/17321516/)

External Links

• [NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/22858)
• [OMIM](https://www.omim.org/entry/400044)
• [Ensembl](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000146738)
• [UniProt](https://www.uniprot.org/uniprot/Q9H0Y5)

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

References