Neurexin 1α structural variants associated with autism

Jin, Yan; Noltner, Katie; Feng, Jinong; Li, Wenyan; Schroer, Richard J.; Skinner, Cindy; Zeng, Weizhi; Schwartz, Charles E.; Sommer, Steve S.

doi:10.1016/j.neulet.2008.04.074

Cited by 144 publications

(97 citation statements)

References 21 publications

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“…We also find that the neurexin-1␣ KO mice display a distinct behavioral phenotype that is consistent in part with cognitive impairments observed in ASDs and schizophrenia, which have been associated with heterozygous deletions of neurexin-1␣ (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). In addition, the moderate extent of the phenotype we observe is in agreement with the viability of neurexin-1␣ KO mice, the fact that other ␣-neurexins are still expressed in neurexin-1␣ KO mice, and the observation that human patients containing a heterozygous deletion of neurexin-1␣ are overall functional (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Although the phenotype of the neurexin-1␣ KO mice is limited, it should be noted that some of the changes we observed are quite dramatic, as discussed below.…”

Section: Discussionsupporting

confidence: 76%

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Etherton¹,

Blaiss²,

Powell³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

406

369

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Deletions in the neurexin-1␣ gene were identified in large-scale unbiased screens for copy-number variations in patients with autism or schizophrenia. To explore the underlying biology, we studied the electrophysiological and behavioral phenotype of mice lacking neurexin-1␣. Hippocampal slice physiology uncovered a defect in excitatory synaptic strength in neurexin-1␣ deficient mice, as revealed by a decrease in miniature excitatory postsynaptic current (EPSC) frequency and in the input-output relation of evoked postsynaptic potentials. This defect was specific for excitatory synaptic transmission, because no change in inhibitory synaptic transmission was observed in the hippocampus. Behavioral studies revealed that, compared with littermate control mice, neurexin-1␣ deficient mice displayed a decrease in prepulse inhibition, an increase in grooming behaviors, an impairment in nestbuilding activity, and an improvement in motor learning. However, neurexin-1␣ deficient mice did not exhibit any obvious changes in social behaviors or in spatial learning. Together, these data indicate that the neurexin-1␣ deficiency induces a discrete neural phenotype whose extent correlates, at least in part, with impairments observed in human patients.autism ͉ neuroligin ͉ schizophrenia ͉ synaptic cell-adhesion ͉ synapse N eurexins are neuronal cell-surface proteins that were identified as receptors for ␣-latrotoxin, a presynaptic toxin that triggers massive neurotransmitter release (1-3). Neurexins are largely presynaptic proteins that form a transsynaptic celladhesion complex with postsynaptic neuroligins (4, 5). Vertebrates express three neurexin genes, each of which includes two promoters that direct the synthesis of the longer ␣-neurexins and the shorter ␤-neurexins (6, 7). Neurexins are expressed in all neurons, and are subject to extensive alternative splicing, generating Ͼ1,000 splice variants, some of which exhibit highly regulated developmental and spatial expression patterns (8).The properties of neurexins suggested that they function as synaptic recognition molecules (1), and mediate transsynaptic interactions via binding to neuroligins (4). In support of this overall concept, ␣-neurexin triple KO mice exhibit major impairments in synaptic transmission that manifest largely, but not exclusively, as presynaptic changes (9-13). Importantly, ␣-neurexin KO mice do not display a major decrease in the number of excitatory synapses, and only a moderate decrease in inhibitory synapses (9, 13). Thus, neurexins appear to be essential components of synaptic function whose roles extend to several different components of synapses.In recent years, enormous progress in human genetics has led to the identification of multiple genes that are linked to autism spectrum disorders (ASDs) and schizophrenia. Interestingly, copy-number variations in the neurexin-1␣ gene (but not the neurexin-1␤ gene) were repeatedly observed in patients with ASDs (14 -21) and schizophrenia (22-25). Because 0.5% of all ASD cases appear to harbor neurexin-1␣ gen...

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Section: Discussionsupporting

confidence: 76%

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Etherton¹,

Blaiss²,

Powell³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

406

369

View full text Add to dashboard Cite

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“…Results from a linkage and copy number variation analysis conducted by the Autism Genome Project Consortium (Szatmari et al, 2007) show that neurexin-1 dysfunction is associated with ASD. This conclusion has been corroborated in multiple linkage analysis studies since (Kim et al, 2008;Marshall et al, 2008) and in analysis of structural variants in the -and -neurexin genes (Zahir et al, 2008;Feng et al, 2006;Yan et al, 2008;Gai et al, 2011;Gauthier et al, 2011). Neurexin knock-out animals have provided insights into the functions of the neurexin family.…”

Section: Neurexin and Neuroligin Deficits In Asdmentioning

confidence: 69%

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

Anand¹,

Amici²,

Ponath³

et al. 2011

Autism - A Neurodevelopmental Journey From Genes to Behaviour

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“…Neurexin gene mutations have been identified in individuals with autism. 82 Levison and El-Husseini 83 reviewed information on the role of the neuroligin)neurexin interaction on synapse maturation and functioning, and the mechanisms whereby structural defects in these proteins may lead to autism.…”

Section: Non-syndromic Causes Of Autismmentioning

confidence: 99%

Genetic causes of syndromic and non‐syndromic autism

Çağlayan

2010

Develop Med Child Neuro

102

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Aims Over the past decade, genetic tests have become available for numerous heritable disorders, especially those whose inheritance follows the Mendelian model. Autism spectrum disorders (ASDs) represent a group of developmental disorders with a strong genetic basis. During the past few years, genetic research in ASDs has been successful in identifying several vulnerability loci and a few cytogenetic abnormalities or single‐base mutations implicated in the causation of autism. Method In this study the literature was reviewed to highlight genotype–phenotype correlations between causal gene mutations or cytogenetic abnormalities and behavioural or morphological phenotypes. Results Based on this knowledge, practical information is offered to help clinicians pursue targeted genetic testing of individuals with autism whose clinical phenotype is suggestive of a specific genetic or genomic aetiology. Interpretation Comprehensive research into the molecular mechanism of autism is required to aid the development of disease‐specific targeted therapies. In order to transfer this recently acquired knowledge into clinical practice, it is critical to define a set of phenotypic inclusion criteria that must be met by affected probands to justify their enrolment in a specific genetic testing programme.

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Neurexin 1α structural variants associated with autism

Cited by 144 publications

References 21 publications

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

Genetic causes of syndromic and non‐syndromic autism

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