Children's Hospital Boston Genotype Phenotype Study Group: Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders

Division of Developmental Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 06/2010; 153B(4):937-47. DOI: 10.1002/ajmg.b.31063
Source: PubMed


Research has implicated mutations in the gene for neurexin-1 (NRXN1) in a variety of conditions including autism, schizophrenia, and nicotine dependence. To our knowledge, there have been no published reports describing the breadth of the phenotype associated with mutations in NRXN1. We present a medical record review of subjects with deletions involving exonic sequences of NRXN1. We ascertained cases from 3,540 individuals referred clinically for comparative genomic hybridization testing from March 2007 to January 2009. Twelve subjects were identified with exonic deletions. The phenotype of individuals with NRXN1 deletion is variable and includes autism spectrum disorders, mental retardation, language delays, and hypotonia. There was a statistically significant increase in NRXN1 deletion in our clinical sample compared to control populations described in the literature (P = 8.9 x 10(-7)). Three additional subjects with NRXN1 deletions and autism were identified through the Homozygosity Mapping Collaborative for Autism, and this deletion segregated with the phenotype. Our study indicates that deletions of NRXN1 predispose to a wide spectrum of developmental disorders.

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Available from: Rachel Hundley, Oct 04, 2015
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    • "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]. "
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    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
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    • "(Boucard et al., 2005). Recent data suggest that heterozygous mutations in NRXN1 represent a susceptibility factor for a broad spectrum of neurological and neuropsychological disorders for example, schizophrenia (Ching et al., 2010; Kirov et al., 2008; Rujescu et al., 2009), ID disorders (McIntosh et al., 2006; Zahir et al., 2008; Zweier et al., 2009), autism, (Gregor et al., 2011) and various other neuropsychiatric disorders (Ching et al., 2010). A number of studies reveal recessive genetic defects in NRXN1 associated with severe ID and dysmorphic features resembling the Pitt–Hopkins like syndrome in some cases (Duong et al., 2012; Harrison et al., 2011; Zweier et al., 2009). "
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    ABSTRACT: We report a consanguineous Pakistani family with a severe congenital microcephaly syndrome resembling Seckel syndrome and Jawad syndrome. The affected individuals in this family were born to consanguineous parents of whom the mother presented with mild intellectual disability (ID), epilepsy and diabetes mellitus. The two living affected brothers presented with microcephaly, white matter disease of the brain, hyponychia, dysmorphic facial features with synophrys, epilepsy, diabetes mellitus and ID. Genotyping with a 250K SNP array in both affected brothers revealed an 18MB homozygous region on chromosome 18p11.21q12.1 encompassing the SCKL2 locus of Seckel and Jawad syndrome. Sequencing of the RBBP8, underlying Seckel and Jawad syndrome, identified the novel mutation c.919A>G, p.Arg307Gly, segregating in a recessive manner in the family. In addition, in the two affected brothers and their mother we have also found a heterozygous 607kb deletion, encompassing exons 13-19 of NRXN1. Bidirectional sequencing of the coding exons of NRXN1 did not reveal any other mutation on the other allele. It thus appears that the phenotype of the mildly affected mother can be explained by the NRXN1 deletion, whereas the more severe and complex microcephalic phenotype of the two affected brothers is due to the simultaneous deletion in NRXN1 and the homozygous missense mutation affecting RBBP8.
    Gene 01/2014; DOI:10.1016/j.gene.2014.01.027 · 2.14 Impact Factor
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    • "The outcome of the autism genome-wide association study projects surprisingly revealed only weak correlations for ASD to common genetic variants, but identified genes with rare single nucleotide polymorphisms (SNPs) or copy number variations that have a considerable impact [96]. Such rare mutations have been found in the α-neurexin coding region of nrxn1[97-99], nrxn3[100] and the signal peptide of β-neurexins [101]. An excess of mutations in these genes is found in patients with ASD [27,102], schizophrenia [103,104] and substance abuse and impulsive behavior [105]. "
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