Neurexin
Neurexins (NRXN) are a family of presynaptic cell adhesion proteins that have roles in connecting neurons at the synapse.
[5] In humans, alterations in genes encoding neurexins are implicated in autism and other cognitive diseases, such as Tourette syndrome and schizophrenia.
[5] In mammals, neurexin is encoded by three different genes (NRXN1, NRXN2, and NRXN3) each controlled by two different promoters, an upstream alpha (α) and a downstream beta (β), resulting in alpha-neurexins 1-3 (α-neurexins 1–3) and beta-neurexins 1-3 (β-neurexins 1–3).
[9] The C terminus of the short intracellular section of both types of neurexins binds to synaptotagmin and to the PDZ (postsynaptic density (PSD)-95/discs large/zona-occludens-1) domains of CASK and Mint.
Trans-synapse, the extracellular LNS domains have a functional region, the hyper-variable surface, formed by loops carrying 3 splice inserts.
[2] This region surrounds a coordinated Ca2+ ion and is the site of neuroligin binding,[10] resulting in a neurexin-neuroligin Ca2+-dependent complex at the junction of chemical synapses.
Over-expression of either of these proteins causes an increase in synapse forming sites, thus providing evidence that neurexin plays a functional role in synaptogenesis.
One possibility is that actin is polymerized on the tail end of β-neurexin, which traps and stabilizes accumulating synaptic vesicles.
In mice, a deletion of dystroglycan causes long-term potentiation impairment and developmental abnormalities similar to muscular dystrophy; however baseline synaptic transmission is normal.
[20] Members of the neurexin family are found across all animals, including basal metazoans such as porifera (sponges), cnidaria (jellyfish) and ctenophora (comb jellies).
Homologues of α-neurexin have also been found in several invertebrate species including Drosophila, Caenorhabditis elegans, honeybees and Aplysia.
[12] In Drosophila melanogaster, NRXN genes (only one α-neurexin) are critical in the assembly of glutamatergic neuromuscular junctions but are much simpler.
A small percentage of ASD patients present with single mutations in genes encoding neuroligin-neurexin cell adhesion molecules.
[22] This provides strong evidence that neurexin deletions result in increased risk of ASDs, and indicate synapse dysfunction as the possible site of autism origin.
[27] Genomic duplications and deletions on a micro-level – known as copy number variants (CNVs) – often underlie neurodevelopmental syndromes.
Genomic-wide scans suggest that individuals with schizophrenia have rare structural variants that deleted or duplicated one or more genes.
[5][26] A recent study shows that NRXN genes 1-3 are essential for survival and play a pivotal and overlapping role with each other in neurodevelopment.
[29] Another study suggests that NLGN4 mutations can be associated with a wide spectrum of neuropsychiatric conditions and that carriers may be affected with milder symptoms.
