HGNC Approved Gene Symbol: NRXN3
Cytogenetic location: 14q24.3-q31.1 Genomic coordinates (GRCh38): 14:78,170,373-79,868,291 (from NCBI)
Neurexins are polymorphic cell surface proteins that are expressed in neurons. Neurexin III is 1 of 3 rat neurexin genes identified by Ushkaryov et al. (1992); the other 2 are neurexin I (600565) and neurexin II (600566). Each gene contains 2 promoters that direct synthesis of alpha- and beta-neurexins.
By screening human brain cDNAs for those encoding proteins larger than 50 kD, Nagase et al. (1998) identified KIAA0743, a cDNA encoding a human homolog of the rat neurexin III-alpha precursor. The predicted 1,061-amino acid KIAA0743 gene product shares 99% identity with rat neurexin III-alpha. Using an ELISA-based procedure to quantify the results of RT-PCR analyses, the authors found that the highest level of KIAA0743 expression was in brain.
In a review, Missler and Sudhof (1998) noted that the highly conserved alpha-neurexin proteins contain an N-terminal signal peptide followed by 3 overall repeats, each composed of 2 similar laminin (LAMA1; 150320)/neurexin/sex hormone-binding globulin (SHBG; 182205), or LNS, domains of approximately 190 residues. The LNS domains are separated from each other by an EGF-like sequence. After the 3 sets of LNSA-EGF-LNSB domains, alpha-neurexins contain an O-glycosylation sequence and a single transmembrane domain, followed by a conserved, relatively short cytoplasmic tail of 55 amino acids. Beta-neurexins are identical to the C-terminal half of alpha-neurexins, but lack 5 of the 6 N-terminal LNS domains and all 3 EGF-like sequences, which are replaced by a short beta-neurexin-specific sequence. NRXN3 has secreted splice variants lacking the conserved intracellular sequences that bind to CASK (300172). In addition to alpha-latrophilin, ligands for alpha-neurexins include neurexophilins (e.g., 604639), whereas the neuroligins (e.g., NLGN2; 606479) are ligands for beta-neurexins and mediate cell adhesion. The C termini of neuroligins also interact with the third PDZ domain of PSD95 (DLG4; 602887). These ligands, like neurexins, are predominantly or exclusively expressed in brain.
Using RT-PCR, Occhi et al. (2002) detected high expression of NRXN3-alpha in human brain, lung, and pancreas, with lower levels in heart, placenta, liver, and kidney. NXRN3-beta showed lower expression compared with NXRN3-alpha. The authors identified and characterized heart-specific NRXN3 splice variants.
By genomic sequence analysis, Tabuchi and Sudhof (2002) determined that the NRXN3 gene contains 24 exons, spans 1.6 Mb, and has very large introns. Exon 1 is more than 2 kb and encodes the first LNS domain and the first EGF-like repeat of alpha-neurexins. Other exons are average in size, with the remaining LNS domains interrupted by at least 1 intron, whereas all EGF-like repeats are encoded in single exons. The last exon, also relatively large, encodes the transmembrane region and cytoplasmic tail. Tabuchi and Sudhof (2002) also described a number of neurexin splice sites.
Rowen et al. (2002) analyzed the structures of the neurexin genes and noted that the CpG island-rich promoter for alpha-neurexins is located upstream of exon 1, whereas the promoter for beta-neurexins, which is also CpG rich, is located downstream of exon 17. They identified 25 exons in NRXN3. When used, the additional exon (23) introduces a stop codon before exon 24, resulting in no translation of transmembrane and cytoplasmic domains and accounting for the secreted forms of NRXN3. There are 5 alternative splice sites for NRXN3-alpha, but only sites 4 and 5 are used to generate variants of NRXN3-beta. The intronic sequences upstream of exon 7 are highly conserved between NRXN1 and NRXN3 and contain consensus binding sites for the neural-specific splicing regulatory protein NOVA1 (602157), the target antigen of the autoimmune disease paraneoplastic opsoclonus myoclonus ataxia. Rowen et al. (2002) concluded that there are a total of 2,208 possible alpha-neurexin transcripts and 42 possible beta-neurexin transcripts. The authors also identified a neuron-restrictive silencer factor (NRSF; 600571)-binding site upstream of the NRXN3-alpha promoter that was not present in the other 5 NRXN promoters.
By genomic sequence analysis, Rowen et al. (2002) mapped the NRXN3 gene to chromosome 14q24.3-q31.1.
In postmortem human brains, Hishimoto et al. (2007) found that expression of alpha-NRXN3 mRNA in frontal cortex was 5-fold higher than beta-NRXN3. Both isoforms were expressed at variable levels in hippocampus, substantia nigra, midbrain, caudate, and putamen. In the cerebellum, beta-NRXN3 expression was over 5-fold higher than alpha-NRXN3 expression. An analysis of different splice variants showed that the soluble NRXN3 isoforms include exon 23, whereas the transmembrane isoforms omit exon 23.
Associations Pending Confirmation
Vaags et al. (2012) reported 4 families in which one or more members had autism spectrum disorder (ASD; 209850) associated with heterozygous deletions of chromosome 14q affecting the NRXN3 gene. The deletions were all different and ranged from 63 to 336 kb. One deletion affected only the NRXN3 alpha isoform, whereas 3 affected both the alpha and beta isoforms. Two families were ascertained from 1,158 Canadian individuals with ASD who were screened for copy number variations across the genome. The third family was 1 of 1,368 ASD cases screened, and the fourth was 1 of 1,796 ASD cases screened. The phenotype was variable, ranging from high-functioning Asperger syndrome to full autism with some pervasive developmental and behavioral problems. In 1 family, the deletion occurred de novo. In the other families, the deletion was inherited from a parent; 1 parent had a broader autism phenotype, 1 self-reported mild autistic-like features, and 1 was normal. In 1 family, 2 of 3 trizygotic triplets with autism carried the deletion; the third unaffected child did not carry the deletion. Small deletions affecting only the alpha isoform were found in 4 of 15,122 controls. The report suggested that deletions affecting the NRXN3 gene may predispose to the development of autism spectrum disorder, but segregation patterns within the families suggested issues of penetrance and expressivity at this locus.
For discussion of a possible association between genetic variation in the NRXN3 gene and alcohol dependence, see 103780.
Using triple alpha-neurexin knockout mice lacking 1 or more of the 3 neurexin genes, Missler et al. (2003) showed that alpha-neurexins are required for normal neurotransmitter release and that deletion of alpha-neurexins impairs the function of synaptic calcium channels. The results indicated a link between synaptic cell adhesion and presynaptic voltage-gated calcium signaling, and suggested that alpha-neurexins organize presynaptic terminals by functionally coupling calcium channels to the presynaptic machinery.
Keum et al. (2018) found that the 129S1 mouse strain exhibited significantly higher observational fear compared with other strains due to a homozygous SNP in Nxrn3 that resulted in a deleterious arg498-to-trp (R498W) substitution. The authors showed that Sst (182450)-expressing neurons controlled observational fear response in the anterior cingulate cortex (ACC) and that Nrxn3 was essential for inhibitory synaptic transmissions from Sst-expressing neurons. Cell-specific deletion analysis demonstrated that the deletion of Nrxn3 or homozygosity for R498W reduced inhibitory synaptic transmission in Sst-expressing neurons, causing elevated observational fear.
Hishimoto, A., Liu, Q.-R., Drgon, T., Pletnikova, O., Walther, D., Zhu, X.-G., Troncoso, J. C., Uhl, G. R. Neurexin 3 polymorphisms are associated with alcohol dependence and altered expression of specific isoforms. Hum. Molec. Genet. 16: 2880-2891, 2007. [PubMed: 17804423] [Full Text: https://doi.org/10.1093/hmg/ddm247]
Keum, S., Kim, A., Shin, J. J., Kim, J.-H., Park, J., Shin, H.-S. A missense variant at the Nrxn3 locus enhances empathy fear in the mouse. Neuron 98: 588-601, 2018. [PubMed: 29681532] [Full Text: https://doi.org/10.1016/j.neuron.2018.03.041]
Missler, M., Sudhof, T. C. Neurexins: three genes and 1001 products. Trends Genet. 14: 20-26, 1998. [PubMed: 9448462] [Full Text: https://doi.org/10.1016/S0168-9525(97)01324-3]
Missler, M., Zhang, W., Rohlmann, A., Kattenstroth, G., Hammer, R. E., Gottmann, K., Sudhof, T. C. Alpha-neurexins couple Ca(2+) channels to synaptic vesicle exocytosis. Nature 423: 939-948, 2003. [PubMed: 12827191] [Full Text: https://doi.org/10.1038/nature01755]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 277-286, 1998. [PubMed: 9872452] [Full Text: https://doi.org/10.1093/dnares/5.5.277]
Occhi, G., Rampazzo, A., Beffagna, G., Danieli, G. A. Identification and characterization of heart-specific splicing of human neurexin 3 mRNA (NRXN3). Biochem. Biophys. Res. Commun. 298: 151-155, 2002. [PubMed: 12379233] [Full Text: https://doi.org/10.1016/s0006-291x(02)02403-8]
Rowen, L., Young, J., Birditt, B., Kaur, A., Madan, A., Philipps, D. L., Qin, S., Minx, P., Wilson, R. K., Hood, L., Graveley, B. R. Analysis of the human neurexin genes: alternative splicing and the generation of protein diversity. Genomics 79: 587-597, 2002. [PubMed: 11944992] [Full Text: https://doi.org/10.1006/geno.2002.6734]
Tabuchi, K., Sudhof, T. C. Structure and evolution of neurexin genes: insight into the mechanism of alternative splicing. Genomics 79: 849-859, 2002. [PubMed: 12036300] [Full Text: https://doi.org/10.1006/geno.2002.6780]
Ushkaryov, Y. A., Petrenko, A. G., Geppert, M., Sudhof, T. C. Neurexins: synaptic cell surface proteins related to the alpha-latrotoxin receptor and laminin. Science 257: 50-56, 1992. [PubMed: 1621094] [Full Text: https://doi.org/10.1126/science.1621094]
Vaags, A. K., Lionel, A. C., Sato, D., Goodenberger, M., Stein, Q. P., Curran, S., Ogilvie, C., Ahn, J. W., Drmic, I., Senman, L., Chrysler, C., Thompson, A., and 15 others. Rare deletions at the neurexin 3 locus in autism spectrum disorder. Am. J. Hum. Genet. 90: 133-141, 2012. [PubMed: 22209245] [Full Text: https://doi.org/10.1016/j.ajhg.2011.11.025]