Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients

Jin, Yan; Oliveira, Guiomar; Coutinho, Ana; Yang, Chaowu; Feng, Jinong; Katz, Cécile; Sram, Jakub P.; Bockholt, Anke; Jones, Ian; Craddock, Nicholas John; Eh, Cook; Vicente, Astrid M.; Sommer, Steve S.

doi:10.1038/sj.mp.4001629

Cited by 296 publications

(233 citation statements)

References 11 publications

(8 reference statements)

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“…An NL3 mutation, R451C, and three NL4 mutations, G99S, K378R and V403M, located in the CLD domain, have been found in autistic patients 11,15 . These residues, corresponding to Arg473, Asp106, Lys414, and Val439 of NL1 respectively, are highly conserved except NL1 Asp106 ( Supplementary Fig.…”

Section: Effects Of the Autism-related Neuroligin Mutationsmentioning

confidence: 99%

“…Aberrant neuroligin genes have been linked to autism 11,15,16,31 , but it remains unclear how the point mutations of neuroligins are related to the genesis of the disease. An NL3 mutation, R451C, and three NL4 mutations, G99S, K378R and V403M, located in the CLD domain, have been found in autistic patients 11,15 .…”

Section: Effects Of the Autism-related Neuroligin Mutationsmentioning

confidence: 99%

“…Two adhesion molecules that have been implicated in the establishment and maturation of synaptic contacts are neuroligins, which are postsynaptic proteins, and neurexins, which are presynaptic proteins [2][3][4][5][6][7] . Polymorphisms in neuroligin and neurexin genes have been associated with several cases of cognitive disorders such as autism and mental retardation [8][9][10][11][12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

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Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Chen

Liu

Shim

et al. 2007

Nat Struct Mol Biol

145

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The heterophilic synaptic adhesion molecules, neuroligins and neurexins, are essential for establishing and maintaining neuronal circuits by modulating the formation and maturation of synapses. The neuroligin-neurexin adhesion is Ca 2+ -dependent and regulated by alternative splicing. We report a 2.4Å structure of the complex between the mouse neuroligin-1 (NL1) cholinesterase-like domain and the mouse neurexin 1β (NX1β) LNS (laminins, neurexins, and sex hormone-binding globulin-like) domain. The structure reveals a delicate neuroligin-neurexin assembly mediated by a hydrophilic, Ca 2+ -mediated, and solvent-supplemented interface, rendering it capable of being modulated by alternative splicing and other regulatory factors. Thermodynamic data support a mechanism where splicing site B of NL1 acts by modulating a salt bridge at the edge of the NL1-NX1β interface. Mapping neuroligin mutations implicated in autism indicates most such mutations are structurally destabilizing, supporting deficient neuroligin biosynthesis and processing as a common cause for this brain disorder.

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Section: Effects Of the Autism-related Neuroligin Mutationsmentioning

confidence: 99%

Section: Effects Of the Autism-related Neuroligin Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Chen

Liu

Shim

et al. 2007

Nat Struct Mol Biol

145

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“…In 2003, a mutation in neuroligin 3 ( NLGN3 ; p.R451C) and a mutation in neuroligin 4X ( NLGN4X ; p.D396 fs) were reported in two unrelated Swedish autism families (Jamain et al., 2003). Since then, several other mutations in the NLGN3 , NLGN4X , and NLGN4Y genes have been reported to be related to autism (Chih, Afridi, Clark, & Scheiffele, 2004; Daoud et al., 2009; Kuroda et al., 2014; Laumonnier et al., 2004; Lawson‐Yuen et al., 2008; Talebizadeh et al., 2006; Yan et al., 2005, 2008). In vitro and in vivo experiments have indicated that the autism‐related neuroligin mutations may affect synapse maturation and function.…”

Section: Introductionmentioning

confidence: 99%

Not all neuroligin 3 and 4X missense variants lead to significant functional inactivation

Zhang

et al. 2017

Brain and Behavior

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IntroductionNeuroligins are postsynaptic cell adhesion molecules that interact with neurexins to regulate the fine balance between excitation and inhibition of synapses. Recently, accumulating evidence, involving mutation analysis, cellular assays, and mouse models, has suggested that neuroligin (NLGN) mutations affect synapse maturation and function. Previously, four missense variations [p.G426S (NLGN3), p.G84R (NLGN4X), p.Q162K (NLGN4X), and p.A283T (NLGN4X)] in four different unrelated patients have been identified by PCR and direct sequencing.MethodsIn this study, we analyzed the functional effect of these missense variations by in vitro experiment via the stable HEK293 cells expressing wild‐type and mutant neuroligin.ResultsWe found that the four mutations did not significantly impair the expression of neuroligin 3 and neuroligin 4X, and also did not measurably inhibit the neurexin 1–neuroligin interaction. These variants might play a modest role in the pathogenesis of autism or might simply be unreported infrequent polymorphisms.ConclusionOur data suggest that these four previously described neuroligin mutations are not primary risk factors for autism.

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“…Multiple genetic changes in Nrxn [84][85][86][87][88][89][90][91][92][93][94] and Nlgn genes [92,93,[95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110] have been found in ASD patients. These changes include (i) point mutations, which cause frame shifts, small deletions, and missense mutations in both coding and promoter regions, (ii) distinct translocation events, and (iii) large-scale deletions of chromosomal DNA containing these gene loci.…”

Section: Neurexins and Neuroliginsmentioning

confidence: 99%

The complex genetics in autism spectrum disorders

Hua

Wei

Zhang

2015

Sci. China Life Sci.

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Autism spectrum disorders (ASD) are a pervasive neurodevelopmental disease characterized by deficits in social interaction and nonverbal communication, as well as restricted interests and stereotypical behavior. Genetic changes/heritability is one of the major contributing factors, and hundreds to thousands of causative and susceptible genes, copy number variants (CNVs), linkage regions, and microRNAs have been associated with ASD which clearly indicates that ASD is a complex genetic disorder. Here, we will briefly summarize some of the high-confidence genetic changes in ASD and their possible roles in their pathogenesis.autism spectrum disorders, genetics, causative genes, copy number variants Citation:Hua R, Wei MP, Zhang C. The complex genetics in autism spectrum disorders. Sci China Life Sci, 2015, 58: 933 -945,

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Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients

Cited by 296 publications

References 11 publications

Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Not all neuroligin 3 and 4X missense variants lead to significant functional inactivation

The complex genetics in autism spectrum disorders

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