The human genes NRXN1, NRXN2, and NRXN3 have been identified as high-confidence candidate susceptibility loci for autism spectrum disorder (SFARI Gene, see below; see also discussion in MIM:209850). Each encodes a single-pass membrane protein that belongs to the neurexin family; the neurexin/neuroligin complex is present at neural synapses and is required for efficient neurotransmission and in the formation of synaptic contacts. There is a single orthologous gene in Drosophila, Dmel\Nrx-1, for which classical amorphic alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Nrx-1 is also orthologous to an additional neurexin gene in human, NRXN4. NRXN1 has also been implicated in Pitt-Hopkins-like syndrome 2 (MIM:614325) and a deletion syndrome associated with susceptibility to schizophrenia (MIM:614332).
Multiple UAS constructs of the human Hsap\NRXN1 gene has been introduced into flies, including wild-type and variants implicated in ASD. See the 'Disease-Implicated Variants' table below.
Animals homozygous for amorphic mutations of Dmel\Nrx-1 typically die before reaching adult stage; larvae exhibit locomotor, neuroanatomy, and neurophysiology defects. RNAi-effected loss of function leads to reduced behavioral flexibility in adults, as shown by severe reversal-learning impairment; it is postulated that this phenotype results from the failure to properly activate Rac1-dependent forgetting. Genetic and physical interactions for Dmel\Nrx-1 have been described; see below and in the Nrx-1 gene report.
NRXN1 is one of a number of genes in human that have been implicated in both autism spectrum disorder and schizophrenia. See the human disease model report 'autism co-occurence with schizophrenia' (FBhh0001356).
[updated Jan. 2022 by FlyBase; FBrf0222196]
Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996, pubmed:8655659; Risch et al., 1999, pubmed:10417292). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (MIM:608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008; pubmed:18698615). [from MIM:209850; 2017.03.18]
The SFARI Gene autism database ( https:gene.sfari.org ) rates the gene-autism associations for NRXN1, NRXN2, and NRXN3 as high confidence (score 1). [2020.11.05]
NRXN1 gene encodes a single-pass type I membrane protein that belongs to the neurexin family. Neurexins are cell-surface receptors that bind neuroligins to form Ca(2+)-dependent neurexin/neuroligin complexes at synapses in the central nervous system. [Gene Cards, NRXN1; 2017.03.18]
Neuroligins function as ligands for the neurexins, which are cell-surface receptors. The Ca(2+)-dependent neurexin/neuroligin complex is present at synapses in the central nervous system, is required for efficient neurotransmission, and is involved in the formation of synaptic contacts (summary by Reissner et al., 2008; pubmed:18812509). [from MIM:600568; 2017.03.18]
Many to one: 3 human to 1 Drosophila. The other human genes are NRXN2 and NRXN3.
High-scoring ortholog of human NRXN1, NRXN2 and NRXN3 (1 Drosophila to 3 human). Dmel\Nrx-1 shares 32-33% identity and 47-49% similarity with the human genes.
