Alternative titles; symbols
HGNC Approved Gene Symbol: NLGN1
Cytogenetic location: 3q26.31 Genomic coordinates (GRCh38): 3:173,395,952-174,294,372 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.31 | {Autism, susceptibility to, 20} | 618830 | Autosomal dominant | 3 |
The NLGN1 gene encodes a transmembrane protein that belongs to the NLGN family of cell-adhesion molecules. NLGN proteins form transsynaptic complexes with presynaptic neurexin molecules (see, e.g, NRXN1, 600565), via the extracellular domain, whereas the NLGN cytoplasmic domain interacts with postsynaptic molecules including PSD95 (DLG4; 602887) and SHANK proteins (see, e.g., SHANK1, 604999) (summary by Nakanishi et al., 2017).
The Ca(2+)-dependent neurexin/neuroligin complex is present at synapses in the central nervous system, is required for efficient neurotransmission, and is involved in the formation of synaptic contacts (summary by Reissner et al., 2008).
Ichtchenko et al. (1995) described neuroligin-1, a neuronal cell surface protein that is enriched in rat synaptic plasma membranes and acts as a splice site-specific ligand for beta-neurexins (see 600565). NLGN1 binds to beta-neurexins only if they lack an insert in the alternatively spliced sequence of the G domain, and not if they contain an insert. The extracellular sequence of rat neuroligin-1 is composed of a catalytically inactive esterase domain homologous to acetylcholinesterase. Ichtchenko et al. (1995) used in situ hybridization to demonstrate that alternative splicing of neurexins at the binding site recognized by neuroligin-1 is highly regulated. These findings support a model whereby alternative splicing of neurexins creates a family of cell surface receptors that confer interactive specificity on their resident neurons.
Kikuno et al. (1999) cloned a human NLGN1 cDNA, which they designated KIAA1070, from a brain cDNA library and found that it encodes a deduced 823-amino acid protein. RT-PCR ELISA detected low NLGN1 expression in adult brain and spinal cord and in all adult brain regions examined. Very low NLGN1 expression was detected in fetal brain and in adult heart, kidney, testis, and ovary, but not in other peripheral tissues examined.
Nakanishi et al. (2017) noted that the NLGN1 gene is highly expressed in brain through the prenatal and postnatal stages.
Using an in vitro system, Scheiffele et al. (2000) demonstrated that mouse neuroligin-1 and -2 (NLGN2; 606479), postsynaptically localized proteins, can trigger the de novo formation of presynaptic structure. Nonneuronal cells engineered to express neuroligins induced morphologic and functional presynaptic differentiation in contacting axons. This activity could be inhibited by addition of a soluble version of beta-neurexin. Furthermore, addition of soluble beta-neurexin to a coculture of defined pre- and postsynaptic central nervous system (CNS) neurons inhibited synaptic vesicle clustering in axons contacting target neurons. These results suggested that neuroligins are part of the machinery employed during the formation and remodeling of CNS synapses.
Using predominantly human and rodent constructs, Graf et al. (2004) found that NRXN1-beta, when expressed in cocultured nonneuronal cells, clustered the postsynaptic proteins gephyrin (GPHN; 603930) and PSD95 (DLG4; 602887), neurotransmitter receptors, and all 4 neuroligins in cocultured rodent hippocampal neurons. The isolated LNS domain of NRXN1-beta was sufficient for this synaptogenic activity when expressed in cells or immobilized on beads. Neuroligin aggregation alone was synaptogenic, but it showed some specificity: neuroligins-1, -3 (NLGN3; 300336), and -4 (NLGN4; 300427) linked only to glutamatergic postsynaptic proteins, but neuroligin-2 linked to both glutamatergic and GABAergic postsynaptic proteins.
Chih et al. (2005) demonstrated that members of the neuroligin family promote postsynaptic differentiation in cultured rat hippocampal neurons. Downregulation of neuroligin isoform expression by RNA interference results in a loss of excitatory and inhibitory synapses. Electrophysiologic analysis revealed a predominant reduction of inhibitory synaptic function. Thus, Chih et al. (2005) concluded that neuroligins control the formation and functional balance of excitatory and inhibitory synapses in hippocampal neurons.
Using affinity chromatography with rat brain proteins, Boucard et al. (2005) identified neuroligin-1 as an endogenous ligand of neurexin 1-alpha and -beta. Further analysis showed that different splice variants of Nlgn1 had different binding specificities: Ngln1 containing an insert in splice site B bound exclusively to neurexin-1-beta lacking an insert in splice site 4, whereas Nlgn1 lacking an insert in splice site B bound to both neurexin-1-alpha and -beta. Neuroligin-1 that bound only beta-neurexin potently stimulated synapse formation, and neuroligin-1 that bound to both alpha- and beta-neurexins promoted synapse expansion. The findings suggested that neuroligin binding to neurexins mediates trans-synaptic cell adhesion with distinct effects.
Chubykin et al. (2005) found that point mutations in 2 surface loops of rat neuroligin-1, when expressed in HEK293 or COS cells, abolished neuroligin-1 binding to rat Nrxn1-beta in cocultured rat hippocampal neurons and blocked synapse formation.
Arac et al. (2007) stated that the extracellular esterase-like domains of neuroligins interact with alpha- and beta-neurexins in a calcium-dependent manner and that splicing at 2 sites in neuregulins strongly modulates their affinity for neurexins. Likewise, extensive alternative splicing in neurexins influences their binding to neuroligins. Arac et al. (2007) presented the crystal structures of rat neuroligin-1 in isolation and in complex with rat Nrxn1-beta. Neuroligin-1 formed a dimer, and 2 Nrxn1-beta monomers bound to 2 identical surfaces on the opposite faces of the neuroligin-1 dimer to form a heterotetramer. The complex included a large binding interface that contained calcium. The sites of alternative splicing in neuroligin-1 and Nrxn1-beta, which alter binding affinity, were positioned nearby the binding interface.
Using rodent hippocampal neurons and cortical slices, Chubykin et al. (2007) showed that Nl1 reinforced activity-dependent excitatory, but not inhibitory, synaptic responses. In contrast, Nl2 (NLGN2) reinforced activity-dependent inhibitory, but not excitatory, synaptic responses. Nl1 and Nl2 were not required for synapse formation.
Reissner et al. (2008) examined the interaction sites of the neurexin/neuroligin complex using mutagenesis studies. The contact area in neurexins is sharply delineated and consists of hydrophobic residues of the LNS domain that surround a calcium-binding pocket. Point mutations that changed electrostatic and shape properties left calcium coordination intact, but completely inhibited neuroligin binding. Alternative splicing in alpha- and beta-neurexins and in neuroligins had a weaker effect on complex formation. In neuroligins, the contact area appeared less distinct, since exchange of a more distant aspartate completely abolished binding to neurexin but many mutations of predicted interface residues had no strong effect on binding. Together with calculations of energy terms for presumed interface hotspots, the study presented a comprehensive structural basis for complex formation of neurexins and neuroligins and their trans-synaptic signaling between neurons.
Kim et al. (2008) used virus-mediated RNA interference to deplete endogenous neuroligin-1 in the lateral nucleus of the amygdala of adult mice and found that neuroligin-1 was required for the storage of associative fear memory. Cellular physiologic studies showed that suppression of neuroligin-1 reduced NMDA receptor (NMDAR; see 138249)-mediated currents and prevented long-term potentiation without affecting basal synaptic connectivity along the thalamo-amygdala pathway. Kim et al. (2008) concluded that persistent expression of neuroligin-1 is required for maintenance of NMDAR-mediated synaptic transmission, which enables normal development of synaptic plasticity and long-term memory in the amygdala.
Wittenmayer et al. (2009) found that presynaptic terminals of cultured Nlgn1 -/- mouse hippocampal neurons remained functionally immature with respect to active zone stability and synaptic vesicle pool size. Conversely, overexpression of Nlgn1 in immature neurons induced formation of presynaptic boutons with hallmarks of mature structures. Nlgn1-induced active zones remained stable in the absence of F-actin. The extracellular domain of Nlgn1 was sufficient to induce assembly of functional presynaptic terminals, whereas the intracellular domain was required for terminal maturation.
Gkogkas et al. (2013) demonstrated that knockout of the eukaryotic translation initiation factor 4E-binding protein-2 (EIF4EBP2; 602224) (an EIF4E (133440) repressor downstream of MTOR (601231)) or EIF4E overexpression leads to increased translation of neuroligins, postsynaptic proteins that are causally linked to autism spectrum disorders (ASDs). Mice with knockout of Eif4ebp2 exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviors (i.e., social interaction deficits, altered communication, and repetitive/stereotyped behaviors). Pharmacologic inhibition of Eif4e activity or normalization of neuroligin-1, but not neuroligin-2, protein levels restored the normal excitation/inhibition ratio and rectified the social behavior deficits. Thus, Gkogkas et al. (2013) concluded that translational control by EIF4E regulates the synthesis of neuroligins, maintaining the excitation-to-inhibition balance, and its dysregulation engenders ASD-like phenotypes.
Stogsdill et al. (2017) demonstrated that astrocyte morphogenesis in the mouse cortex depends on direct contact with neuronal processes and occurs in parallel with the growth and activity of synaptic circuits. The neuroligin family cell adhesion proteins NL1, NL2 (606479), and NL3 (300336), which are expressed by cortical astrocytes, control astrocyte morphogenesis through interactions with neuronal neurexins. Furthermore, in the absence of astrocytic NL2, the formation and function of cortical excitatory synapses are diminished, whereas inhibitory synaptic function is enhanced. Stogsdill et al. (2017) concluded that their findings highlighted a theretofore undescribed mechanism of action for neuroligins and linked astrocyte morphogenesis to synaptogenesis.
By radiation hybrid analysis, Kikuno et al. (1999) mapped the human NLGN1 gene to chromosome 3.
In 2 brothers, born of unrelated parents (family AU0729), with susceptibility to autism-20 (AUTS20; 618830), Nakanishi et al. (2017) identified a heterozygous missense mutation in the NLGN1 gene (P89L; 600568.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; it was inherited from the mother, who had obsessive-compulsive disorder and anxiety. Further investigations of larger cohorts revealed 3 heterozygous missense variants (L269P, 600568.0002; G297E, 600568.0003, and H795Y) in the NLGN1 gene in 3 of over 2,500 families with autism spectrum disorder (ASD) and an additional fourth heterozygous missense variant (T90I) in 2 of 362 children with ASD. Detailed clinical features of these 4 patients were not reported. Based on in silico predictions, P89L, L269P, and G297E were classified as 'high-risk' alleles, and H795Y and T90I were classified as 'low-risk' alleles. All variants, except H795Y, were located in the extracellular domain, but they were not predicted to interfere with NLGN1-neurexin binding. The P89L, L269P, and G297E variants were not found in the ExAC, Exome Sequencing Project, or 1000 Genomes Project databases. In vitro functional expression studies in COS-7 cells showed that these 3 mutant proteins were trapped in the endoplasmic reticulum (ER) and failed to traffic normally to the plasma membrane. There was also decreased expression of the mutant proteins compared to wildtype, suggesting ER-associated degradation, in COS-7 cells and primary neurons transfected with the mutations. Neurons transfected with these 3 mutations showed decreased numbers of dendritic spines, suggesting impaired spine formation compared to controls.
Hu et al. (2012) found that C. elegans neurexin-1 (600565) and neuroligin mediated a retrograde synaptic signal that inhibited neurotransmitter release at neuromuscular junctions. Retrograde signaling was induced in mutants lacking a muscle mRNA and was blocked in mutants lacking NLG1 or NRX1. Release was rapid and abbreviated when the retrograde signal was on, whereas release was slow and prolonged when retrograde signaling was blocked. The retrograde signal adjusted release kinetics by inhibiting exocytosis of synaptic vesicles that are distal to the site of calcium entry. Inhibition of release was mediated by increased presynaptic levels of tomosyn (STXBP5; 604586), an inhibitor of synaptic vesicle fusion.
Nakanishi et al. (2017) found that heterozygous mice carrying the P89L Nlgn1 variant (600568.0001) showed abnormal social behavior and impaired spatial memory compared to controls, reminiscent of autistic features in humans. Increased repetitive behavior was not observed. Neuropathologic examination of mutant mice showed decreased Nlgn1 expression (30% reduction compared to wildtype), but there were no differences in dendritic spine numbers in hippocampal cell cultures derived from mutant mice.
In 2 brothers, born of unrelated parents (family AU0729), with susceptibility to autism-20 (AUTS20; 618830), Nakanishi et al. (2017) identified a heterozygous c.266C-T transition in the NLGN1 gene, resulting in a pro89-to-leu (P89L) substitution at a highly conserved residue in the extracellular domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; it was inherited from the mother who had obsessive-compulsive disorder and anxiety. The variant was not found in the ExAC, Exome Variant Server, or 1000 Genomes Project databases. The variant, which affected a proline-rich loop of the esterase-homology domain, was predicted to have a destabilizing effect on protein structure and folding. In vitro functional expression studies in COS-7 cells showed that the mutant protein was trapped in the ER and failed to traffic normally to the plasma membrane. There was also decreased expression of the mutant protein compared to wildtype, suggesting ER-associated degradation, in both COS-7 cells and transfected neurons. Transfection neurons showed decreased numbers of dendritic spines, suggesting impaired spine formation compared to controls.
In a patient (13876p.1) with susceptibility to autism-20 (AUTS20; 618830), Nakanishi et al. (2017) identified a heterozygous T-to-C transition in the NLGN1 gene, resulting in a leu269-to-pro (L269P) substitution in the extracellular domain. The mutation was found by direct sequencing of the NLGN1 gene in a cohort of over 2,500 families with autism. The variant was not found in the ExAC, Exome Variant Server, or 1000 Genomes Project databases. In vitro functional expression studies in COS-7 cells showed that the mutant protein was trapped in the ER and failed to traffic normally to the plasma membrane. There was also decreased expression of the mutant protein compared to wildtype, suggesting ER-associated degradation, in both COS-7 cells and transfected neurons. Transfection neurons showed decreased numbers of dendritic spines, suggesting impaired spine formation compared to controls. The variant was inherited from the father; clinical details of the father were not provided.
In a patient (11045p.1) with susceptibility to autism-20 (AUTS20; 618830), Nakanishi et al. (2017) identified a heterozygous G-to-A transition in the NLGN1 gene, resulting in a gly297-to-glu (G297E) substitution in the extracellular domain. The mutation was found by direct sequencing of the NLGN1 gene in a cohort of over 2,500 families with autism. The variant was not found in the ExAC, Exome Variant Server, or 1000 Genomes Project databases. In vitro functional expression studies in COS-7 cells showed that the mutant protein (mouse ortholog G288E) was trapped in the ER and failed to traffic normally to the plasma membrane. There was also decreased expression of the mutant protein compared to wildtype, suggesting ER-associated degradation, in both COS-7 cells and transfected neurons. Transfection neurons showed decreased numbers of dendritic spines, suggesting impaired spine formation compared to controls. The variant was inherited from the mother; clinical details of the mother were not provided.
This variant is classified as a variant of unknown significance because its contribution to susceptibility to autism-20 (618830) has not been confirmed.
In 16-year-old monozygotic twin boys, born of consanguineous parents, with autism, Tejada et al. (2019) identified a homozygous c.74T-A transversion in the NLGN1 gene, resulting in a leu25-to-ter (L25X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the unaffected parents. Functional studies of the variant and studies of patient cells were not performed. The authors noted that the variant may result in the production of a truncated protein or be subject to nonsense-mediated mRNA decay.
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Boucard, A. A., Chubykin, A. A., Comoletti, D., Taylor, P., Sudhof, T. C. A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to alpha- and beta-neurexins. Neuron 48: 229-236, 2005. [PubMed: 16242404] [Full Text: https://doi.org/10.1016/j.neuron.2005.08.026]
Chih, B., Engelman, H., Scheiffele, P. Control of excitatory and inhibitory synapse formation by neuroligins. Science 307: 1324-1328, 2005. Note: Erratum: Science 308: 1413 only, 2005. [PubMed: 15681343] [Full Text: https://doi.org/10.1126/science.1107470]
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Chubykin, A. A., Liu, X., Comoletti, D., Tsigelny, I., Taylor, P., Sudhof, T. C. Dissection of synapse induction by neuroligins: effect of a neuroligin mutation associated with autism. J. Biol. Chem. 280: 22365-22374, 2005. [PubMed: 15797875] [Full Text: https://doi.org/10.1074/jbc.M410723200]
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Graf, E. R., Zhang, X., Jin, S.-X., Linhoff, M. W., Craig, A. M. Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell 119: 1013-1026, 2004. [PubMed: 15620359] [Full Text: https://doi.org/10.1016/j.cell.2004.11.035]
Hu, Z., Hom, S., Kudze, T., Tong, X.-J., Choi, S., Aramuni, G., Zhang, W., Kaplan, J. M. Neurexin and neuroligin mediate retrograde synaptic inhibition in C. elegans. Science 337: 980-984, 2012. [PubMed: 22859820] [Full Text: https://doi.org/10.1126/science.1224896]
Ichtchenko, K., Hata, Y., Nguyen, T., Ullrich, B., Missler, M., Moomaw, C., Sudhof, T. C. Neuroligin 1: a splice site-specific ligand for beta-neurexins. Cell 81: 435-443, 1995. [PubMed: 7736595] [Full Text: https://doi.org/10.1016/0092-8674(95)90396-8]
Kikuno, R., Nagase, T., Ishikawa, K., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 197-205, 1999. [PubMed: 10470851] [Full Text: https://doi.org/10.1093/dnares/6.3.197]
Kim, J., Jung, S.-Y., Lee, Y. K., Park, S., Choi, J.-S., Lee, C. J., Kim, H.-S., Choi, Y.-B., Scheiffele, P., Bailey, C. H., Kandel, E. R., Kim, J.-H. Neuroligin-1 is required for normal expression of LTP and associative fear memory in the amygdala of adult animals. Proc. Nat. Acad. Sci. 105: 9087-9092, 2008. [PubMed: 18579781] [Full Text: https://doi.org/10.1073/pnas.0803448105]
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Reissner, C., Klose, M., Fairless, R., Missler, M. Mutational analysis of the neurexin/neuroligin complex reveals essential and regulatory components. Proc. Nat. Acad. Sci. 105: 15124-15129, 2008. [PubMed: 18812509] [Full Text: https://doi.org/10.1073/pnas.0801639105]
Scheiffele, P., Fan, J., Choih, J., Fetter, R., Serafini, T. Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101: 657-669, 2000. [PubMed: 10892652] [Full Text: https://doi.org/10.1016/s0092-8674(00)80877-6]
Stogsdill, J. A., Ramirez, J., Liu, D., Kim, Y. H., Baldwin, K. T., Enustun, E., Ejikeme, T., Ji, R.-R., Eroglu, C. Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. Nature 551: 192-197, 2017. [PubMed: 29120426] [Full Text: https://doi.org/10.1038/nature24638]
Tejada, M.-I., Elcoroaristizabal, X., Ibarluzea, N., Botella, M.-P., de la Hoz, A.-B., Ocio, I. A novel nonsense homozygous variant in the NLGN1 gene found in a pair of monozygotic twin brothers with intellectual disability and autism. (Letter) Clin. Genet. 95: 339-340, 2019. [PubMed: 30460678] [Full Text: https://doi.org/10.1111/cge.13466]
Wittenmayer, N., Korber, C., Liu, H., Kremer, T., Varoqueaux, F., Chapman, E. R., Brose, N., Kuner, T., Dresbach, T. Postsynaptic neuroligin1 regulates presynaptic maturation. Proc. Nat. Acad. Sci. 106: 13564-13569, 2009. [PubMed: 19628693] [Full Text: https://doi.org/10.1073/pnas.0905819106]