Disease relevance of NLGN1

• A large French family including members affected by nonspecific X-linked mental retardation, with or without autism or pervasive developmental disorder in affected male patients, has been found to have a 2-base-pair deletion in the Neuroligin 4 gene (NLGN4) located at Xp22.33 [1].

Psychiatry related information on NLGN1

• Our findings suggest that the previously identified mutations in neuroligin genes are likely to be relevant for the neuro-developmental defects in autism-spectrum disorders and mental retardation since they impair the function of a synaptic cell adhesion molecule [2].

High impact information on NLGN1

• In situ hybridization reveals that alternative splicing of neurexins at the site recognized by neuroligin 1 is highly regulated [3].
• Here we describe neuroligin 1, a neuronal cell surface protein that is enriched in synaptic plasma membranes and acts as a splice site-specific ligand for beta-neurexins [3].
• Neuroligation: building synapses around the neurexin-neuroligin link [4].
• It is thought to be triggered by members of the neuroligin family of postsynaptic cell adhesion proteins, which may form transsynaptic contacts with presynaptic alpha- and beta-neurexins and have been implicated in the etiology of autism [5].
• Neuroligin, butyrylcholinesterase, and acetylcholinesterase are members of the alpha,beta-hydrolase fold family of proteins sharing sequence similarity and common tertiary structures [6].

Biological context of NLGN1

• Here, we report a detailed molecular genetic analysis of NLGN1, NLGN3, NLGN4, and NLNG4Y in the Finnish autism sample [7].
• Neuroligin-1 has a unique N-linked glycosylation pattern in the neuroligin family, and glycosylation and its processing modify neuroligin activity [8].
• A recent study has implicated two X-chromosomal neuroligin genes, NLGN3 and NLGN4, as having an etiological role in autism, having identified a frameshift mutation in one gene and a substitution mutation in the other, segregating in multiplex autism spectrum families (Jamain et al. [2003: Nat Genet 34:27-29]) [9].
• Yet since NLGN1 is involved in synaptogenesis in the central nervous system, altered gene dosage is a good candidate for mental retardation as a recurrent feature of dup(3q) syndrome [10].
• The breakpoint within NLGN1 is unique for this patient, and the contribution of NLGN1 disruption to the phenotype of this patient remains unclear [10].

Anatomical context of NLGN1

• In contrast, the mRNA encoding for neurexin-Ibeta, the heterophilic ligand of the AChE-homologous neuronal cell surface protein neuroligin, was drastically lower in embryonic transgenic spinal cord than in controls [11].
• The postsynaptic adhesion molecules neuroligin-1, neuroligin-2, and SynCAM1 provide target-derived signals leading to the assembly of presynaptic terminals [12].
• The Cys mutation causes defective neuroligin trafficking, leading to retention of the protein in the endoplasmic reticulum [13].
• Neuroligin is a neural cell-adhesion molecule of the post-synapse, which binds to the presynapse molecule neurexin to form a heterotypic intercellular junction [14].
• Overexpression of neuroligin 4 cDNA in COS-7 cells led to the production of a 110 kDa protein [15].

Associations of NLGN1 with chemical compounds

• Incomplete processing of the protein and enzymatic removal of the oligosaccharides chain or the terminal sialic acids from neuroligin-1 enhance its activity, whereas deglycosylation of neurexin-1beta did not alter its association capacity [8].
• The Arg473Cys-neuroligin-1 mutation modulates NMDA mediated synaptic transmission and receptor distribution in hippocampal neurons [16].
• T28C12.4, which encodes a protein with limited homology to human neuroligin, was also specific to ethanol stress [17].
• Functional excitatory synapses in HEK293 cells expressing neuroligin and glutamate receptors [18].

Other interactions of NLGN1

• Family-based association analysis in 100 families with autism spectrum disorders yielded only modest associations at NLGN1 (rs1488545, P=0.002), NLGN3 (DXS7132, P=0.014), and NLGN4 (DXS996, P=0.031) [7].
• X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family [1].
• The 3D model of the GOPC PDZ domain/neuroligin C-terminal peptide complex was constructed with the aid of the molecular dynamics simulation method [14].
• GOPC interacts with many other proteins, such as the Wnt receptors Frizzled 8 and neuroligin via its PDZ domain [14].
• We demonstrate that addition of the S4 insert selectively reduces the ability of neurexin-1beta to cluster neuroligin-1/3/4 and glutamatergic postsynaptic proteins, although clustering of neuroligin-2 and GABAergic postsynaptic proteins remain strong [19].

Analytical, diagnostic and therapeutic context of NLGN1

• Dissection of synapse induction by neuroligins: effect of a neuroligin mutation associated with autism [20].
• Moreover, the results of fluorescence in situ hybridization (FISH) analysis with BAC probes suggest a disruption of the NLGN1 gene at the distal end of the duplication in 3q26.31 in the patient [10].
• Northern-blot analysis revealed expression of neuroligin 4 in heart, liver, skeletal muscle and pancreas, but barely at all in brain [15].
• We took this opportunity recording for the first-time synaptic currents in human embryonic kidney 293 (HEK293) cells transfected with neuroligin and the N-methyl-d-aspartate or AMPA receptor subunits in a co-culture with rat cerebellar granule cells [18].
• We have characterized, in vitro, interactions between hippocampal neuronal cells and silica microbeads coated with synthetic, fluid, lipid bilayer membranes containing the glycosylphosphatidyl inositol (GPI)-linked extracellular domain of the postsynaptic membrane protein neuroligin-1 [21].

References