Disruption of Neurexin 1 Associated with Autism Spectrum Disorder

Molecular Neurogenetics Unit, Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2008; 82(1):199-207. DOI: 10.1016/j.ajhg.2007.09.011
Source: PubMed


Autism is a neurodevelopmental disorder of complex etiology in which genetic factors play a major role. We have implicated the neurexin 1 (NRXN1) gene in two independent subjects who display an autism spectrum disorder (ASD) in association with a balanced chromosomal abnormality involving 2p16.3. In the first, with karyotype 46,XX,ins(16;2)(q22.1;p16.1p16.3)pat, NRXN1 is directly disrupted within intron 5. Importantly, the father possesses the same chromosomal abnormality in the absence of ASD, indicating that the interruption of alpha-NRXN1 is not fully penetrant and must interact with other factors to produce ASD. The breakpoint in the second subject, with 46,XY,t(1;2)(q31.3;p16.3)dn, occurs approximately 750 kb 5' to NRXN1 within a 2.6 Mb genomic segment that harbors no currently annotated genes. A scan of the NRXN1 coding sequence in a cohort of ASD subjects, relative to non-ASD controls, revealed that amino acid alterations in neurexin 1 are not present at high frequency in ASD. However, a number of rare sequence variants in the coding region, including two missense changes in conserved residues of the alpha-neurexin 1 leader sequence and of an epidermal growth factor (EGF)-like domain, respectively, suggest that even subtle changes in NRXN1 might contribute to susceptibility to ASD.

Download full-text


Available from: David L Pauls,
  • Source
    • "The possibility that alterations of synaptic functions could lead to autism was noted by the phenotypic overlap between autism, fragile X syndrome, and Rett syndrome (Zoghbi, 2003; Belmonte and Bourgeron, 2006). The synaptic abnormality hypothesis is further substantiated by the identification of mutations affecting synaptic cell adhesion molecules, NRXN1, NLGN3/4 and SHANK3, in addition to mutations in synaptic proteins, CNT- NAP2, CACNA1C, CNTN3/4 and PCDH9/10 (Durand et al., 2007a; Kim et al., 2008; Bakkaloglu et al., 2008; Alarcón et al., 2008; Arking et al., 2008; Marshall et al., 2008; Morrow et al., 2008). Furthermore , several genes linked to an autistic predisposition have been related to synaptic functioning. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BTBR mice exhibit several autistic-like behaviors and are currently used as a model for understanding mechanisms that may be responsible for the pathogenesis of autism. Ras/Raf/ERK1/2 signaling has been suggested to play an important role in neural development, learning, memory, and cognition. Two studies reported that a deletion of a locus on chromosome 16 containing the mitogen-activated protein kinase 3 (MAPK3) gene, which encodes ERK1, is associated with autism. In the present study, Ras/Raf/ERK1/2 signaling was found to be up-regulated in BTBR mice relative to matched control B6 mice, to further suggest involvement in the pathogenesis of autism. To further characterize the developmental pattern of Ras/Raf/ERK1/2 signaling, varying stages during development were sampled to reveal an up-regulation in newborn and 2-week old BTBR mice relative to age-matched B6 mice. By the age of 3-week, Ras/Raf/ERK1/2 signaling in the brain of BTBR mice was unaltered relative to B6 mice, with this trend maintained in 6-week samples. These results suggest that the alteration of Ras/Raf/ERK signaling in the early developmental stages in mice could contribute to the noted autistic phenotype. Furthermore, these findings support the value of BTBR mice to serve as a human analogue for autistic etiological research and aid in a better understanding of the developmental mechanisms of autism.
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 12/2014; 39. DOI:10.1016/j.ijdevneu.2014.01.006 · 2.58 Impact Factor
  • Source
    • "Treatment of PC12 cells with PPA or BA caused down regulation of FMR1 gene expression (Table 10). Neurexin 1 (NRXN1) is another gene considered to be causal for ASD [127], [128] which was also down regulated following BA administration. Many genes associated with ASD are also involved in the neuroligin-neurexin interaction at the glutamate synapse [129], [28]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alterations in gut microbiome composition have an emerging role in health and disease including brain function and behavior. Short chain fatty acids (SCFA) like propionic (PPA), and butyric acid (BA), which are present in diet and are fermentation products of many gastrointestinal bacteria, are showing increasing importance in host health, but also may be environmental contributors in neurodevelopmental disorders including autism spectrum disorders (ASD). Further to this we have shown SCFA administration to rodents over a variety of routes (intracerebroventricular, subcutaneous, intraperitoneal) or developmental time periods can elicit behavioral, electrophysiological, neuropathological and biochemical effects consistent with findings in ASD patients. SCFA are capable of altering host gene expression, partly due to their histone deacetylase inhibitor activity. We have previously shown BA can regulate tyrosine hydroxylase (TH) mRNA levels in a PC12 cell model. Since monoamine concentration is known to be elevated in the brain and blood of ASD patients and in many ASD animal models, we hypothesized that SCFA may directly influence brain monoaminergic pathways. When PC12 cells were transiently transfected with plasmids having a luciferase reporter gene under the control of the TH promoter, PPA was found to induce reporter gene activity over a wide concentration range. CREB transcription factor(s) was necessary for the transcriptional activation of TH gene by PPA. At lower concentrations PPA also caused accumulation of TH mRNA and protein, indicative of increased cell capacity to produce catecholamines. PPA and BA induced broad alterations in gene expression including neurotransmitter systems, neuronal cell adhesion molecules, inflammation, oxidative stress, lipid metabolism and mitochondrial function, all of which have been implicated in ASD. In conclusion, our data are consistent with a molecular mechanism through which gut related environmental signals such as increased levels of SCFA's can epigenetically modulate cell function further supporting their role as environmental contributors to ASD.
    PLoS ONE 08/2014; 9(8):e103740. DOI:10.1371/journal.pone.0103740 · 3.23 Impact Factor
  • Source
    • "Several mutations in neurexin–neuroligin genes have been linked to ASDs (Jamain et al. 2003; Laumonnier et al. 2004; Yan et al. 2005; Kim et al. 2008). One of these, the missense mutation R451C of the gene encoding for the postsynaptic adhesion protein Neuroligin3 (Nlgn3), found in two families with children affected by ASDs (Jamain et al. 2003), has been introduced by gene targeting in mice (Tabuchi et al. 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuroligins are postsynaptic adhesion molecules that interacting with presynaptic neurexins ensure the cross-talk between pre- and postsynaptic specializations. Rare mutations in neurexin–neuroligin genes have been linked to autism spectrum disorders (ASDs). One of these, the R451C mutation of the gene encoding for Neuroligin3 (Nlgn3), has been found in patients with familial forms of ASDs. Animals carrying this mutation (NL3R451C knock-in mice) exhibit impaired social behaviors, reminiscent of those observed in ASD patients, associated with major alterations in both GABAergic and glutamatergic transmission, which vary among different brain regions and at different developmental stages. Here, pair recordings from parvalbumin- (PV) expressing basket cells and spiny neurons were used to study GABAergic synaptic signaling in layer IV barrel cortex of NL3R451C mutant mice. We found that the R451C mutation severely affects the probability of GABA release from PV-expressing basket cells, responsible for controlling via thalamo-cortical inputs the feed-forward inhibition. No changes in excitatory inputs to parvalbumin-positive basket cells or spiny neurons were detected. These data clearly show that primary targets of the NL3 mutation are PV-expressing basket cells, independently of the brain region where they are localized. Changes in the inhibitory gate of layer IV somatosensory cortex may alter sensory processing in ASD patients leading to misleading sensory representations with difficulties to combine pieces of information into a unified perceptual whole.
    07/2014; 2(7). DOI:10.14814/phy2.12077
Show more