Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia

Abstract

Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including NRXN1 have been associated with these neurodevelopmental disorders, but no such associations have been reported for NRXN2 or NRXN3. From resequencing the three neurexin genes in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94), we identified a truncating mutation in NRXN2 in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in SCZ, supporting the notion of a common genetic mechanism in these disorders.

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

“…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.…”

Phenotypic spectrum and genotype–phenotype correlations of NRXN1 exon deletions

“…Deletions and loss-of-function point mutations of NRXN1 have been linked to autism, schizophrenia and intellectual disability. [13][14][15]21,23 More recently, intragenic rearrangements of NRXN1 have been described and associated with a wide spectrum of developmental disorders. 23,24 There is a significantly higher prevalence of NRXN1 deletions among clinical samples when compared with control populations.…”

“…3,4 Copy number variants (CNVs) of NRXN1 The NRXN1 gene has been shown to have a fundamental role in synaptogenesis and synaptic maintenance, as well as neurotransmitter release and the function of voltage-gated calcium channels in the synapses of brainstem and neocortex. [5][6][7][8] Variants of NRXN1 have been associated with cognitive impairment, 9,10 schizophrenia, [11][12][13][14][15] nicotine dependence, 16,17 alcohol dependence 18 and ASDs. [19][20][21][22][23] More recently, patients with smaller, intragenic deletions of the NRXN1 gene have been identified.…”

Adult Neurogenesis and Psychiatric Disorders

“…Furthermore, significant numbers of dentate gyrus granule cells were histologically and electrophysiologically immature, more than would be predicted based on proliferation rates and the tempo of normal development, and these mice showed severe impairments in working memory . Neurexins (NRXNs) and neuroligins (NLGNs) are families of synaptic proteins, which are known to be risk factors for schizophrenia (Novak et al 2009;Rujescu et al 2009;Ikeda et al 2010;Gauthier et al 2011;Mozhui et al 2011;Sun et al 2011;Yue et al 2011). These proteins are synaptic cell-adhesion molecules involved in various neuronal processes, including differentiation, maturation, stabilization, and plasticity of both inhibitory and excitatory synapses (Bang and Owczarek 2013).…”