HGNC Approved Gene Symbol: NRXN2
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38): 11:64,606,174-64,723,197 (from NCBI)
The neurexins are neuronal proteins that function as cell adhesion molecules during synaptogenesis and in intercellular signaling (summary by Rowen et al., 2002).
Neurexins are polymorphic cell surface proteins that are expressed in neurons. Neurexin II is 1 of 3 rat neurexin genes identified by Ushkaryov et al. (1992); the other 2 are neurexin I (NRXN1; 600565) and neurexin III (NRXN3; 600567). Each gene contains 2 promoters that direct synthesis of alpha- and beta-neurexins. By analysis of a 1.2-Mb region flanking the MEN1 gene (613733) on chromosome 11q13, Bergman et al. (1999) identified MCG36, a human gene similar to rat neurexin II-alpha.
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.
By genomic sequence analysis, Tabuchi and Sudhof (2002) determined that the NRXN2 gene contains 23 exons, has very large introns, and spans 106 kb, making it a relatively small gene compared to NRXN1 and NRXN3. 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 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 24 exons in NRXN2. There are 5 alternative splice sites for NRXN2-alpha, but only site 4 appears to be used to generate variants of NRXN2-beta. Rowen et al. (2002) concluded that there are a total of 2,208 possible alpha-neurexin transcripts and 42 possible beta-neurexin transcripts. They 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, Bergman et al. (1999) mapped the NRXN2 gene to chromosome 11q13.
Associations Pending Confirmation
In a boy of European ancestry with autism spectrum disorder (209850), Gauthier et al. (2011) identified a heterozygous 1-bp deletion (c.2733delT, NM_138732.2) in the NRXN2 gene. The mutation resulted in premature termination at the end of the fourth LNS domain, removing nearly half of the neurexin-2-alpha protein, including the binding sites for neuroligins and leucine-rich repeat transmembrane neuronal proteins (LRRTM) in LNS6, the transmembrane domain, and the intracellular domain. In vitro functional expression studies in COS-7 cells showed that the mutant protein was unable to bind its usual partners, and in vitro studies in neuronal culture showed a loss of synaptogenic activity with lack of clustering of postsynaptic components. The findings were consistent with a loss of function. The mutation was inherited from the patient's father, who had severe language delay. A maternal aunt of the boy's father had schizophrenia, but DNA was not available from her. The patient was identified from a cohort of 142 patients with autism who were screened for mutations in the NRXN1, NRXN2, and NRXN3 genes.
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.
Koh et al. (2021) found that deletion of the long (alpha) isoform of nrxn2a (nrxn2aa -/-), the zebrafish ortholog of mammalian Nrxn2, resulted in motor axonal defects in maternal-zygotic, but not in zygotic, nrxn2aa -/- zebrafish, as nrxn2aa was maternally provided and expressed in zebrafish. Furthermore, nrxn2aa -/- and nrxn2aa -/+ embryos obtained from crossing maternal-zygotic nrxn2aa -/- females and nrxn2aa -/+ males also had motor axonal defects due to the lack of maternally provided nrxn2aa, suggesting that expression of 1 functional nrxn2aa allele was insufficient to compensate for the loss of maternally provided nrxn2aa. Mechanistically, neuromuscular junctions (NMJs) were affected in maternal-zygotic nrxn2aa -/- fish, with defects in synapse formation caused by a cell-autonomous delay in motor axon outgrowth, leading to locomotor defects. Zygotic nrxn2aa was required for maintenance of the zebrafish NMJ. As a result, loss of maternally contributed nrxn2aa affected NMJ maintenance and body growth of zebrafish from early juvenile to adult stages. NMJ defects were transient and juvenile zebrafish were able to partially recover from the defects, but adult maternal-zygotic nrxn2aa -/- fish developed features of progressive muscular atrophy, similar to that described in patients with spinal muscular atrophy (SMA). In addition, despite their phenotypic normalcy compared to maternal-zygotic nrxn2aa -/- fish, adult zygotic nrxn2aa -/- mutants displayed elevated anxiety-like behaviors.
Bergman, L., Silins, G., Grimmond, S., Hummerich, H., Stewart, C., Little, P., Hayward, N. A 500-kb sequence-ready cosmid contig and transcript map of the MEN1 region on 11q13. Genomics 55: 49-56, 1999. [PubMed: 9888998] [Full Text: https://doi.org/10.1006/geno.1998.5625]
Gauthier, J., Siddiqui, T. J., Huashan, P., Yokomaku, D., Hamdan, F. F., Champagne, N., Lapointe, M., Spiegelman, D., Noreau, A., Lafreniere, R. G., Fathalli, F., Joober, R., and 9 others. Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Hum. Genet. 130: 563-573, 2011. [PubMed: 21424692] [Full Text: https://doi.org/10.1007/s00439-011-0975-z]
Koh, A., Tao, S., Goh, Y. J., Chaganty, V., See, K., Purushothaman, K., Orban, L., Mathuru, A. S., Wohland, T., Winkler, C. A Neurexin2aa deficiency results in axon pathfinding defects and increased anxiety in zebrafish. Hum. Molec. Genet. 29: 3765-3780, 2021. [PubMed: 33276371] [Full Text: https://doi.org/10.1093/hmg/ddaa260]
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]
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]