This report describes Pitt-Hopkins-like syndrome 2 (PTHSL2); PTHSL2 exhibits autosomal recessive inheritance. The human gene implicated in this disease, NRXN1, 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 second gene in human, NRXN3. NRXN1 has also been implicated in a deletion syndrome associated with susceptibility to schizophrenia (MIM:614332) and as an autism susceptibility locus (FBhh0000516).
A UAS construct of the wild-type human Hsap\NRXN1 gene has been introduced into flies, but has not been characterized.
Animals homozygous for amorphic mutations of Dmel\Nrx-1 typically die before reaching adult stage. Larvae exhibit locomotor, neurophysiology, and neuroanatomy defects, including decreased number of synaptic boutons in NMJs; overexpression results in increased bouton number. Genetic and physical interactions for Dmel\Nrx-1 have been described; see below and in the Nrx-1 gene report.
[updated Apr. 2020 by FlyBase; FBrf0222196]
[PITT-HOPKINS-LIKE SYNDROME 2; PTHSL2](https://omim.org/entry/614325)
[NEUREXIN I; NRXN1](https://omim.org/entry/600565)
Pitt-Hopkins syndrome is characterized by mental retardation, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea (Zweier et al., 2007; pubmed:17436255). [from MIM:610954; 2019.02.27]
A severe mental retardation syndrome resembling Pitt-Hopkins syndrome; autistic behaviors and recurrent seizures may also be present. [from MIM:614325; 2019.02.27]
Pitt-Hopkins-like syndrome-2 (PTHSL2) is caused by compound heterozygous mutation in the NRXN1 gene. [from MIM:614325; 2019.02.27]
Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility to autism, schizophrenia (SCZD17), developmental delay, intellectual disability, and dysmorphic features. The phenotype is highly variable and shows incomplete penetrance (summary by Dabell et al., 2013; pubmed:23495017). [from MIM:614325; 2019.02.27]
The NRXN1 gene encodes a single-pass type I membrane protein that belongs to the neurexin family. [Gene Cards, NRXN1; 2017.03.18]
Neurexins are presynaptic proteins that help to connect neurons at the synapse. They are located mostly on the presynaptic membrane and contain a single transmembrane domain. The extracellular domain interacts with proteins in the synaptic cleft, most notably neuroligin, while the intracellular cytoplasmic portion interacts with proteins associated with exocytosis. Neurexin and neuroligin "shake hands," resulting in the connection between the two neurons and the production of a synapse. Neurexins mediate signaling across the synapse, and influence the properties of neural networks by synapse specificity. (HGNC Gene group, Neurexins, https://www.genenames.org/data/genegroup/#!/group/1582)
Neurexins, including NRXN1, are cell-surface receptors that bind neuroligins to form a Ca(2+)-dependent neurexin/neuroligin complex at synapses in the central nervous system. This transsynaptic complex is required for efficient neurotransmission and is involved in the formation of synaptic contacts (Reissner et al., 2008; pubmed:18812509). [from MIM:600565; 2019.02.27]
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.
