Relevance to Autism

Recurrent mutations in the NRXN1 gene have been identified in individuals with ASD as described below. Numerous studies have demonstrated a statistically significant enrichment of NRXN1 deletions in ASD cases compared to controls [10 in 2195 cases vs. none in 2519 controls (permuted P-value 0.002) in Glessner et al., 2009; 9 in 1771 cases vs. none in 2539 controls (P-value 3.3 E-04) in Bucan et al., 2009; an excess of exonic NRNX1 CNVs in 996 cases compared to 4,964 controls ((P-value 7.7E-4) in Pinto et al., 2010; 7 exonic deletions in 2,588 cases vs. 1 in 2,670 controls (P-value 0.032) in Girirajan et al., 2013]. A similar enrichment of NRXN1 deletions have been repeatedly observed in cohorts composed of cases with a spectrum of neurodevelopmental disorders, including ASD [9 exonic NRXN1 deletions in 3,540 cases vs. 10 in 51,939 controls (P-value 8.9E-07) in Ching et al., 2010; exonic NRXN1 deletions observed in 0.11% of cases compared to 0.02% of controls (P-value 6.08E-07) in Dabell et al., 2013; NRXN1 deletions in 30 cases vs. 9 controls (simulated P-value of 0.00005) in Coe et al., 2014; P<0.0001 in 19,263 cases and 15,264 controls in Lowther et al., 2016]. Multiple studies have also reported point mutations in NRXN1 in individuals with ASD (Feng et al., 17034946; Kim et al., 2008; Yan et al., 2008; Duong et al., 2012; Liu et al., 2012; Camacho-Garcia et al., 2012), including de novo loss-of-function variants in two probands from simplex families (Iossifov et al., 2012; Stessman et al., 2017). Biallelic mutations in NRXN1 have also been implicated in Pitt-Hopkins-like syndrome 2, an autosomal recessive intellectual disability syndrome (Zweier et al., 2009; Harrison et al., 2011). A polymorphism located in the 3' UTR of NRXN1 was found to influence white matter volume and sensorimotor function in a cohort of healthy individuals in Voineskos et al., 2011 (PMID 21687627).

Molecular Function

Neurexins function in the vertebrate nervous system as cell adhesion molecules and receptors. Two neurexin genes are among the largest known in human (NRXN1 and NRXN3). By using alternate promoters, splice sites and exons, predictions of hundreds or even thousands of distinct mRNAs have been made.

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References

Model Summary

Nrxn1- alpha null rats show increased hyperactivity levels and decrease in learning and memory.

References