HGNC Approved Gene Symbol: NRXN1
Cytogenetic location: 2p16.3 Genomic coordinates (GRCh38): 2:49,918,503-51,032,132 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p16.3 | {Schizophrenia, susceptibility to, 17} | 614332 | 3 | |
| Pitt-Hopkins-like syndrome 2 | 614325 | Autosomal recessive | 3 |
Neurexins, including NRXN1, are cell-surface receptors that bind neuroligins (see NLGN1; 600568) to form a Ca(2+)-dependent neurexin/neuroligin complex at synapses in the central nervous system. This transsynaptic complex is required for efficient neurotransmission and is involved in the formation of synaptic contacts (Reissner et al., 2008).
Ushkaryov et al. (1992) identified the neurexins in the course of cloning the presynaptic receptor for alpha-latrotoxin. Three neurexin genes, designated NRXN1, NRXN2 (600566), and NRXN3 (600567), were identified in a rat brain cDNA library. Rat neurexins were expressed at significant levels only in brain.
Ichtchenko et al. (1995) observed that each neurexin gene has 2 independent promoters which generate 2 classes of mRNAs: the longer mRNAs encode alpha-neurexins and the shorter mRNAs encode beta-neurexins. Thus, 6 principal neurexin isoforms, called neurexins I-alpha to III-beta, result, of which neurexin I-alpha corresponds to the high molecular weight component of the alpha-latrotoxin receptor.
Ullrich et al. (1995) found that the 6 rat neurexin isoforms are coexpressed in neurons and are distributed differentially in various brain regions. Neurexins display a remarkable evolutionarily conserved pattern of extensive alternative splicing. As a result, the total number of neurexins in brain probably exceeds 2,000 (Ullrich et al., 1995). Neurexins contain epidermal growth factor-like sequences and domains homologous to the G domain repeats of laminin A (LAMA; 150320), indicating a function in cell-cell interactions.
By screening human brain cDNAs for those encoding proteins larger than 50 kD, Nagase et al. (1998) identified KIAA0578, a cDNA encoding a human homolog of the rat neurexin I-alpha precursor. The KIAA0578 cDNA contained an open reading frame encoding a protein of at least 1,373 amino acids. By SDS-PAGE, the authors determined that the in vitro transcribed/translated product of the cDNA has a molecular mass greater than 100 kD. RT-PCR revealed that KIAA0578 was expressed in heart and brain. Kleiderlein et al. (1998) identified a human neurexin I-beta cDNA (CCGFB60) in a collection of brain cDNAs containing CCG repeats.
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 NRXN1 gene contains 24 exons, spans 1.1 Mb, and has very large introns. Exon 1 is more than 2 kb in size and encodes the first LNS domain and the first EGF-like repeat of alpha-neurexins. Other exons are of average 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 neurexin gene structure 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. There are 5 alternative splice sites for NRXN1-alpha, but only sites 4 and 5 are used to generate variants of NRXN1-beta. Highly conserved intronic sequences upstream of exon 7 in NRXN1 and NRXN3 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. 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 analysis of a radiation hybrid panel, Nagase et al. (1998) mapped the NRXN1 gene to chromosome 2.
Hartz (2008) mapped the NRXN1 gene to chromosome 2p16.3 based on an alignment of the NRXN1 sequence (GenBank AB011150) with the genomic sequence (build 36.1).
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, 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.
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.
Reissner et al. (2008) examined 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 the complex formation of neurexins and neuroligins and their transsynaptic signaling between neurons.
Autosomal Recessive Pitt-Hopkins-Like Syndrome 2
In a girl with Pitt-Hopkins-like syndrome-2 (PTHSL2; 614325), Zweier et al. (2009) identified compound heterozygosity for 2 mutations in the NRXN1 gene (600565.0001 and 600565.0002). The patient was 18 years old at the time of the report. She had normal growth parameters but had severe mental retardation, acquired walking at age 2 years, and showed developmental regression after the first years. She also had hyperbreathing and autistic behavior. Seizures were not present, and brain MRI was normal. Other features included decreased reflexes in the upper extremities, constipation, and mild facial dysmorphism.
In 2 sisters with a severe early-onset mental retardation syndrome and severe epilepsy, Harrison et al. (2011) identified compound heterozygous deletions on chromosome 2p16.3 exclusively affecting the NRXN1 gene (600565.0004 and 600565.0005). In addition, both girls had a heterozygous paternally inherited 742-kb duplication at chromosome 5q35.1 including 4 genes, which was thought to be a coincidental finding. The phenotype was characterized by onset of epilepsy in infancy followed by mental retardation. Both girls had hypotonia, and only 1 learned to walk at age 5 years. The older sister had episodes of hyperventilation, and the younger had breath-holding spells. Other features in both girls included an abnormal sleep-wake cycle, stereotyped behavior, gastroesophageal reflux with poor growth, constipation, early-onset puberty, pulmonary stenosis, and scoliosis. Brain MRI was normal in the older sister.
Susceptibility to Autism and Mental Retardation Syndromes
Zahir et al. (2008) reported a boy with mild mental retardation, autistic features, multiple vertebral abnormalities, and unusual facies who had a de novo submicroscopic heterozygous 320-kb deletion of chromosome 2p16.3 (614332). The deletion included part of the NRXN1 gene that codes for the NRXN1-alpha promoter and exons 1 through 5, but the NRXN1-beta promoter and the region surrounding it were intact. The findings suggested that correct dosage of NRXN1-alpha is important for normal neurologic development. Although the child had severe language impairment, poor communication, inappropriate social behaviors, tendency to live in his own world, and strict adherence to routine, he did not meet the full criteria for autism spectrum disorder by testing.
Kim et al. (2008) implicated the NRXN1 gene in 2 unrelated subjects who displayed an autism spectrum disorder (see 614332) in association with a balanced chromosomal abnormality involving chromosome 2p16.3. In one of the subjects, NRXN1 was disrupted within intron 5. The father possessed the same chromosomal abnormality in the absence of autism, indicating that the interruption was not fully penetrant and must interact with other factors to produce autism. The breakpoint in the second subject occurred approximately 750 kb 5-prime to NRXN1 within a 2.6-Mb genomic segment that contained no annotated genes. A scan of the NRXN1 coding sequence in a cohort of autistic subjects, relative to non-autistic controls, revealed that amino acid alterations in neurexin-1 are not present at high frequency in autism. However, a number of rare sequence variants in the coding region, including 2 missense changes in conserved residues of the NRXN1 leader sequence and of an epidermal growth factor (EGF)-like domain, respectively, suggested that even subtle changes in NRXN1 might contribute to susceptibility to autism.
Using microarray analysis, Schaaf et al. (2012) identified heterozygous intragenic deletions of the NRXN1 gene in 20 (0.25%) of 8,051 patients referred for intellectual disability, autism spectrum disorder, or seizures. Two additional cases with intragenic NRXN1 deletions were also ascertained. The deletions ranged in size from 17 to 913 kb, deleting between 2 and 13 exons. None of the breakpoints were recurrent, except in sibs. Seven individuals had intronic deletions, which were of uncertain significance. The 17 patients with exonic deletions showed a wide range of phenotypes, including delayed psychomotor development/intellectual disability (93%), infantile hypotonia (59%), autism spectrum disorders (56%), and seizures (53%). Attention deficit-hyperactivity disorder was also commonly observed. Congenital malformations and dysmorphic features were not consistent. Three deletions occurred de novo, and 9 were inherited from a parent. Eight (89%) of the 9 parents from whom a deletion was inherited had a history of learning disabilities and/or neuropsychiatric disease. Deletions of the C-terminal region were associated with increased head size and a high frequency of seizure disorders compared to N-terminal deletions.
Dabell et al. (2013) identified 34 probands with heterozygous deletions of chromosome 2p16.3 involving exons of the NRXN1 gene from a large cohort of 30,065 samples submitted for oligonucleotide-based array covering the NRXN1 gene who were referred for intellectual disability, developmental delay, and/or multiple congenital anomalies. Clinical features were available for 27 patients who had different deletions ranging in size from 40 to 586 kb. The vast majority of the deletions affected the NRXN1-alpha isoforms. There was wide phenotypic variability, but at least 4 features were shared by the majority of patients: developmental delay, speech delay, abnormal behavior including autism spectrum disorder, and some degree of dysmorphism. In addition, 16% of patients had seizures, and heart and skeletal anomalies were sometimes observed. Eight parents of these patients also carried the deletion, some of whom showed neurocognitive defects and some of whom were normal, indicating incomplete penetrance. The frequency of 2p16.3 deletions in the probands (0.11%) was significantly higher than that observed in controls (0.02%) (p = 6.08 x 10(-7)).
Chen et al. (2013) found that deletion in the NRXN1 region was enriched in autism spectrum disorder and neurodevelopmental disorder cohorts compared to controls. Deletions in both affected and control individuals were clustered in the 5-prime portion of NRXN1 and its immediate upstream region. Chen et al. (2013) mapped and analyzed the breakpoints of 32 deletions. The deletion breakpoints displayed frequent microhomology (68.8%, 2-19 bp), suggested predominant mechanisms of DNA replication error and/or microhomology-mediated end joining. Long terminal repeat (LTR) elements, unique non-B-DNA structures, and MEME-defined sequence motifs were significantly enriched, but Alu and LINE sequences were not. Importantly, small-size inverted repeats (minus self chains, minus sequence motifs, and partial complementary sequences) were significantly overrepresented in the vicinity of NRXN1 region deletion breakpoints, suggesting that, although they are not interrupted by the deletion process, such inverted repeats can predispose a region to genomic instability by mediating single-strand DNA looping via the annealing of partially reverse complementary strands and the promoting of DNA replication fork stalling and DNA replication error.
Susceptibility to Schizophrenia 17
In 1 of 93 individuals with schizophrenia (SCZD17; 614332) screened by array comparative genomic hybridization (CGH), Kirov et al. (2008) identified a heterozygous 0.25-Mb deletion on chromosome 2p16.3 spanning the promoter and first exon of the NRXN1 gene. The deletion was not found in 372 controls, but was also present in an affected sib and their unaffected mother. The authors noted that although the mother did not present to psychiatry, she was described as 'odd and neurotic' by the psychiatrist treating her children, suggesting that she may have had subclinical features of the disorder, such as a schizotypal personality.
By array CGH of 150 individuals with schizophrenia and 268 controls, Walsh et al. (2008) identified a heterozygous 115-kb deletion on chromosome 2p16.3 disrupting the NRXN1 gene in a pair of identical twins monozygotic for childhood-onset schizophrenia.
By microarray analysis to screen the NRXN1, NRXN2, and NRXN3 genes for copy number variants (CNV) in 2,977 European patients with schizophrenia and 33,746 European controls, Rujescu et al. (2009) identified 66 deletions and 5 duplications in the NRXN1 gene: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. The CNVs occurred throughout the gene, there was no common breakpoint, and they varied in size from 18 to 420 kb. No CNVs were found in the NRXN2 or NRXN3 genes. By restricting the association analysis to CNVs that disrupted exons, they identified a significant association with a high odds ratio (p = 0.0027; OR 8.97; 0.24% cases vs 0.015% controls). Rujescu et al. (2009) suggested that NRXN1 deletions affecting exons may confer risk of schizophrenia.
In a Hungarian woman with disorganized type schizophrenia, Gauthier et al. (2011) identified a heterozygous de novo mutation in the NRXN1 gene (600565.0003). In vitro expression studies in COS-7 cells and cultured hippocampal cells showed that the mutant NRXN1 protein was not expressed at the cell surface and was retained in the cytoplasm. Functional studies using rodent cDNA showed that the mutant protein failed to bind partners important in synaptic transmission and showed no synaptogenic activity in a neuronal culture assay. The findings were consistent with a loss of function and haploinsufficiency for the NRXN1 allele. The patient was identified from a cohort of 143 patients with schizophrenia screened for mutations in the NRXN1, NRXN2, and NRXN3 genes.
Alpha-latrotoxin is a potent neurotoxin from black widow spider venom that binds to presynaptic receptors and causes massive neurotransmitter release. In rat, 2 alpha-latrotoxin receptors have been identified: neurexin I-alpha, which binds the toxin in a calcium-dependent manner, and CIRL/latrophilin, which binds in a calcium-independent manner. Geppert et al. (1998) isolated the mouse neurexin I-alpha gene and found that it contains a large first exon of more than 1.5 kb that extends to the first site of alternative splicing in the coding region. To evaluate the importance of neurexin I-alpha in alpha-latrotoxin action, Geppert et al. (1998) generated mice carrying a deletion of the first exon of the neurexin I-alpha gene. Homozygous mutant mice lacked neurexin I-alpha, although the levels of neurexin I-beta were unaffected. The mutant mice were viable and fertile, and were indistinguishable in appearance from wildtype animals. The only abnormality observed was that female knockout mice were less able to attend to litters, leading to the death of more pups independent of pup genotype. Geppert et al. (1998) found that alpha-latrotoxin binding to brain membranes from mutant mice was decreased by almost 50% compared with wildtype membranes. In cultured hippocampal neurons from mutant mice, the toxin was still capable of activating neurotransmission. However, measurements of glutamate release from synaptosomes indicated a major decrease in the amount of release triggered by alpha-latrotoxin in the presence of calcium. The authors concluded that neurexin I-alpha is not essential for alpha-latrotoxin action but contributes to toxin action when calcium is present. They suggested that the action of alpha-latrotoxin may be mediated by independent parallel pathways.
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.
By electrophysiologic studies, Etherton et al. (2009) found that hippocampal slices from Nrxn1-null mice had a selective decrease in spontaneous miniature excitatory postsynaptic current frequency compared to controls, but without a change in inhibitory postsynaptic current frequency. These changes correlated with a decrease in excitatory synaptic strength and a decrease in the input-output relation of evoked postsynaptic potentials. However, amplitude of the postsynaptic currents was unchanged. Similar findings were observed in whole-cell voltage-clamp studies. Compared to wildtype littermates, Nrxn1-null mice showed impaired prepulse inhibition, suggesting a defect in sensorimotor gating and abnormal circuit function in the central nervous system, as well as increased grooming and impaired nest building. However, mutant mice showed normal social interaction and normal anxiety-like behavior, locomotor activity, and spatial learning. Motor learning was increased compared to controls. These findings suggested changes that specifically affected organized behavior without an overall loss of brain performance.
Hu et al. (2012) found that C. elegans neurexin-1 and neuroligin (600568) 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 (604586), an inhibitor of synaptic vesicle fusion.
In a girl with Pitt-Hopkins-like syndrome-2 (PTHSL2; 614325), Zweier et al. (2009) identified compound heterozygosity for 2 mutations in the NRXN1 gene: a 180-kb deletion, resulting in the deletion of exons 1 to 4, and a 2936C-G transversion in exon 15, resulting in a ser979-to-ter (S979X; 600565.0002) substitution. The patient was 18 years old at the time of the report. She had normal growth parameters but had severe mental retardation, acquired walking at age 2 years, and showed developmental regression after the first years. She also had hyperbreathing and autistic behavior. Seizures were not present, and brain MRI was normal. Other features included decreased reflexes in the upper extremities, constipation, and mild facial dysmorphism, including broad mouth, strabismus, and protruding tongue with drooling.
For discussion of the ser979-to-ter (S979X) mutation in the NRXN1 gene that was found in compound heterozygous state in a patient with Pitt-Hopkins-like syndrome-2 (PTHSL2; 614325) by Zweier et al. (2009), see 600565.0001.
In a Hungarian woman with schizophrenia-17 (SCZD17; 614332), Gauthier et al. (2011) identified a heterozygous de novo 4-bp insertion (4205insACGG) in exon 22 of the NRXN1 gene, resulting in a frameshift and premature termination affecting both major isoforms. The mutation was predicted to result in a protein lacking the C-terminal transmembrane and cytoplasmic domains. The patient had normal development, later developed disorganized type schizophrenia, and was identified from a cohort of 143 patients with schizophrenia. The mutation was not found in 285 controls. In vitro expression studies in COS-7 cells and cultured hippocampal cells showed that the mutant NRXN1 protein was not expressed at the cell surface and was retained in the cytoplasm. Functional studies using rodent cDNA showed that the mutant protein failed to bind partners important in synaptic transmission and showed no synaptogenic activity in a neuronal culture assay. The findings were consistent with haploinsufficiency for the NRXN1 allele.
In 2 sisters with early-onset severe mental retardation syndrome and severe epilepsy (PTHSL2; 614325), Harrison et al. (2011) identified compound heterozygous deletions on chromosome 2p16.3, exclusively affecting the NRXN1 gene. Array CGH analysis of the older sister showed a 79-kb deletion encompassing exons 20 and 21 inherited from the unaffected mother, and a 287-kb deletion (600565.0005) encompassing the alpha promoter and exons 1 through 5 inherited from the unaffected father. The other affected sister was also found to carry both deletions. The 79-kb deletion is predicted to cause a frameshift and premature termination in exon 22, most likely resulting in nonsense-mediated mRNA decay and lack of both the alpha- and beta-isoforms of NRXN1. In addition, both girls had a heterozygous paternally inherited 742-kb duplication at chromosome 5q35.1 including 4 genes, which was thought to be a coincidental finding. The phenotype was characterized by onset of severe epilepsy in infancy followed by severe mental retardation. Both girls had hypotonia, and only 1 learned to walk at age 5 years. The older sister had episodes of hyperventilation, and the younger had breath-holding spells. Other features in both girls included an abnormal sleep-wake cycle, stereotyped behavior, gastroesophageal reflux with poor growth, constipation, early-onset puberty, pulmonary stenosis, and scoliosis. Brain MRI was normal in the older sister.
For discussion of the 287-kb deletion in the NRXN1 gene that was found in compound heterozygous state in sisters with early-onset severe mental retardation syndrome and severe epilepsy (PTHSL2; 614325) by Harrison et al. (2011), see 600565.0004.
Arac, D., Boucard A. A., Ozkan, E., Strop, P., Newell, E., Sudhof, T. C., Brunger, A. T. Structures of neuroligin-1 and the neuroligin-1/neurexin-1-beta complex reveal specific protein-protein and protein-Ca(2+) interactions. Neuron 56: 992-1003, 2007. [PubMed: 18093522] [Full Text: https://doi.org/10.1016/j.neuron.2007.12.002]
Chen, X., Shen, Y., Zhang, F., Chiang, C., Pillalamarri, V., Blumenthal, I., Talkowski, M., Wu, B.-L., Gusella, J. F. Molecular analysis of a deletion hotspot in the NRXN1 region reveals the involvement of short inverted repeats in deletion CNVs. Am. J. Hum. Genet. 92: 375-386, 2013. [PubMed: 23472757] [Full Text: https://doi.org/10.1016/j.ajhg.2013.02.006]
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]
Dabell, M. P., Rosenfeld, J. A., Bader, P., Escobar, L. F., El-Khechen, D., Vallee, S. E., Dinulos, M. B. P., Curry, C., Fisher, J., Tervo, R., Hannibal, M. C., Siefkas, K., and 21 others. Investigation of NRXN1 deletions: clinical and molecular characterization. Am. J. Med. Genet. 161A: 717-731, 2013. [PubMed: 23495017] [Full Text: https://doi.org/10.1002/ajmg.a.35780]
Etherton, M. R., Blaiss, C. A., Powell, C. M., Sudhof, T. C. Mouse neurexin-1-alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc. Nat. Acad. Sci. 106: 17998-18003, 2009. [PubMed: 19822762] [Full Text: https://doi.org/10.1073/pnas.0910297106]
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]
Geppert, M., Khvotchev, M., Krasnoperov, V., Goda, Y., Missler, M., Hammer, R. E., Ichtchenko, K., Petrenko, A. G., Sudhof, T. C. Neurexin I-alpha is a major alpha-latrotoxin receptor that cooperates in alpha-latrotoxin action. J. Biol. Chem. 273: 1705-1710, 1998. [PubMed: 9430716] [Full Text: https://doi.org/10.1074/jbc.273.3.1705]
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]
Harrison, V., Connell, L., Hayesmoore, J., McParland, J., Pike, M. G., Blair, E. Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters. Am. J. Med. Genet. 155A: 2826-2831, 2011. [PubMed: 21964664] [Full Text: https://doi.org/10.1002/ajmg.a.34255]
Hartz, P. A. Personal Communication. Baltimore, Md. 10/23/2008.
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]
Kim, H.-G., Kishikawa, S., Higgins, A. W., Seong, I.-S., Donovan, D. J., Shen, Y., Lally, E., Weiss, L. A., Najm, J., Kutsche, K., Descartes, M., Holt, L., and 14 others. Disruption of neurexin 1 associated with autism spectrum disorder. Am. J. Hum. Genet. 82: 199-207, 2008. [PubMed: 18179900] [Full Text: https://doi.org/10.1016/j.ajhg.2007.09.011]
Kirov, G., Gumus, D., Chen, W., Norton, N., Georuieva, L., Sari, M., O'Donovan, M. C., Erdogan, F., Owen, M. J., Ropers, H. H., Ullmann, R. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum. Molec. Genet. 17: 458-465, 2008. [PubMed: 17989066] [Full Text: https://doi.org/10.1093/hmg/ddm323]
Kleiderlein, J. J., Nisson, P. E., Jessee, J., Li, W.-B., Becker, K. G., Derby, M. L., Ross, C. A., Margolis, R. L. CCG repeats in cDNAs from human brain. Hum. Genet. 103: 666-673, 1998. Note: Erratum: Hum. Genet. 104: 113 only, 1999. [PubMed: 9921901] [Full Text: https://doi.org/10.1007/s004390050889]
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., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 31-39, 1998. [PubMed: 9628581] [Full Text: https://doi.org/10.1093/dnares/5.1.31]
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]
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]
Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O. P. H., Barnes, M. R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., and 41 others. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum. Molec. Genet. 18: 988-996, 2009. [PubMed: 18945720] [Full Text: https://doi.org/10.1093/hmg/ddn351]
Schaaf, C. P., Boone, P. M., Sampath, S., Williams, C., Bader, P. I., Mueller, J. M., Shchelochkov, O. A., Brown, C. W., Crawford, H. P., Phalen, J. A., Tartaglia, N. R., Evans, P., and 12 others. Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions. Europ. J. Hum. Genet. 20: 1240-1247, 2012. [PubMed: 22617343] [Full Text: https://doi.org/10.1038/ejhg.2012.95]
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]
Ullrich, B., Ushkaryov, Y. A., Sudhof, T. C. Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron 14: 497-507, 1995. [PubMed: 7695896] [Full Text: https://doi.org/10.1016/0896-6273(95)90306-2]
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]
Walsh, T., McClellan, J. M., McCarthy, S. E., Addington, A. M., Pierce, S. B., Cooper, G. M., Nord, A. S., Kusenda, M., Malhotra, D., Bhandari, A., Stray, S. M., Rippey, C. F., and 24 others. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320: 539-543, 2008. [PubMed: 18369103] [Full Text: https://doi.org/10.1126/science.1155174]
Zahir, F. R., Baross, A., Delaney, A. D., Eydoux, P., Fernandes, N. D., Pugh, T., Marra, M. A., Friedman, J. M. A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1-alpha. (Letter) J. Med. Genet. 45: 239-243, 2008. [PubMed: 18057082] [Full Text: https://doi.org/10.1136/jmg.2007.054437]
Zweier, C., de Jong, E. K., Zweier, M., Orrico, A., Ousager, L. B., Collins, A. L., Bijlsma, E. K., Oortveld, M. A. W., Ekici, A. B., Reis, A., Schenck, A., Rauch, A. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am. J. Hum. Genet. 85: 655-666, 2009. [PubMed: 19896112] [Full Text: https://doi.org/10.1016/j.ajhg.2009.10.004]