Human Gene Module / Chromosome X / NLGN3

NLGN3neuroligin 3

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
18 / 32
Rare Variants / Common Variants
27 / 5
Aliases
NLGN3, HNL3,  ASPGX1,  AUTSX1,  KIAA1480
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
Xq13.1
Associated Disorders
-
Relevance to Autism

Studies have found rare single gene variations in the NLGN3 gene in autism. However, other studies claimed to find no rare variations in the NLGN3 gene in autism patients, although one of these found several silent variations. One study (Ylisaukko-oja et al., 2005) found a genetic association between an NLGN3 variant and autism in a sample of Finnish autism families, and another study (Yu et al., 2011) found a genetic association between an NLGN3 variant and autism in the Chinese Han population. This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant.

Molecular Function

This gene encodes a member of a family of neuronal cell-adhesion proteins located at the postsynaptic side of the synapse. Members of this family may act as splice site-specific ligands for beta-neurexins and may be involved in the formation and remodeling of central nervous system synapses.

Reports related to NLGN3 (32 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Jamain S , et al. (2003) Yes -
2 Negative Association Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands. Vincent JB , et al. (2004) Yes -
3 Negative Association NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population. Gauthier J , et al. (2004) Yes -
4 Positive Association Analysis of four neuroligin genes as candidates for autism. Ylisaukko-oja T , et al. (2005) Yes -
5 Recent Recommendation The Arg473Cys-neuroligin-1 mutation modulates NMDA mediated synaptic transmission and receptor distribution in hippocampal neurons. Khosravani H , et al. (2005) No -
6 Recent Recommendation Expression patterns of neurexin-1 and neuroligins in brain and retina of the chick embryo: Neuroligin-3 is absent in retina. Paraoanu LE , et al. (2005) No -
7 Recent Recommendation A mutation linked with autism reveals a common mechanism of endoplasmic reticulum retention for the alpha,beta-hydrolase fold protein family. De Jaco A , et al. (2006) No -
8 Negative Association Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection. Blasi F , et al. (2006) Yes -
9 Recent Recommendation A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Tabuchi K , et al. (2007) No -
10 Negative Association No evidence for involvement of genetic variants in the X-linked neuroligin genes NLGN3 and NLGN4X in probands with autism spectrum disorder on high... Wermter AK , et al. (2008) Yes -
11 Recent Recommendation Differential expression of neuroligin genes in the nervous system of zebrafish. Davey C , et al. (2010) No -
12 Recent Recommendation Neuroligin trafficking deficiencies arising from mutations in the alpha/beta-hydrolase fold protein family. De Jaco A , et al. (2010) No -
13 Positive Association A sex-specific association of common variants of neuroligin genes (NLGN3 and NLGN4X) with autism spectrum disorders in a Chinese Han cohort. Yu J , et al. (2011) Yes -
14 Recent Recommendation Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Etherton M , et al. (2011) No -
15 Support Identification of Four Novel Synonymous Substitutions in the X-Linked Genes Neuroligin 3 and Neuroligin 4X in Japanese Patients with Autistic Spect... Yanagi K , et al. (2012) Yes -
16 Support Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder. Steinberg KM , et al. (2012) Yes -
17 Support Using whole-exome sequencing to identify inherited causes of autism. Yu TW , et al. (2013) Yes -
18 Negative association Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population. Liu Y , et al. (2013) Yes -
19 Recent Recommendation Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling. Fldy C , et al. (2013) No -
20 Recent Recommendation Developmental regulation of GABAergic signalling in the hippocampus of neuroligin 3 R451C knock-in mice: an animal model of Autism. Pizzarelli R and Cherubini E (2013) No -
21 Support Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Jiang YH , et al. (2013) Yes -
22 Support Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders. Kenny EM , et al. (2013) Yes -
23 Negative association Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients. Xu X , et al. (2014) Yes -
24 Recent Recommendation Autism-related neuroligin-3 mutation alters social behavior and spatial learning. Jaramillo TC , et al. (2014) No -
25 Recent recommendation Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors. Rothwell PE , et al. (2014) No -
26 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. Redin C , et al. (2014) No -
27 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
28 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
29 Recent Recommendation Integrated systems analysis reveals a molecular network underlying autism spectrum disorders. Li J , et al. (2015) Yes -
30 Recent recommendation Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Sanders SJ , et al. (2015) Yes -
31 Recent recommendation Modulation of excitation on parvalbumin interneurons by neuroligin-3 regulates the hippocampal network. Polepalli JS , et al. (2017) No -
32 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
Rare Variants   (27)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1351C>T p.Arg451Cys missense_variant Familial Maternal Multiplex 12669065 Jamain S , et al. (2003)
A>G p.(=) synonymous_variant - - - 15274046 Vincent JB , et al. (2004)
C>G p.(=) synonymous_variant - - - 15274046 Vincent JB , et al. (2004)
c.222C>T p.(=) synonymous_variant Familial - Multiplex 16077734 Ylisaukko-oja T , et al. (2005)
G>A p.(=) synonymous_variant - - - 16508939 Blasi F , et al. (2006)
G>A p.(=) synonymous_variant - - - 16508939 Blasi F , et al. (2006)
G>A p.(=) synonymous_variant - - - 16508939 Blasi F , et al. (2006)
G>A p.(=) synonymous_variant - - - 16508939 Blasi F , et al. (2006)
G>A p.(=) synonymous_variant - - - 16508939 Blasi F , et al. (2006)
c.2189G>A p.Thr632Ala missense_variant Familial Maternal Multiplex 16508939 Blasi F , et al. (2006)
c.727+47G>C - intron_variant Unknown - Unknown 22934180 Yanagi K , et al. (2012)
c.1698G>A p.(=) synonymous_variant Unknown - Unknown 22934180 Yanagi K , et al. (2012)
- - intron_variant Unknown - Multiplex 23020841 Steinberg KM , et al. (2012)
- - intron_variant Unknown - Multiplex 23020841 Steinberg KM , et al. (2012)
- - intron_variant Unknown - Multiplex 23020841 Steinberg KM , et al. (2012)
- - intron_variant Unknown - Multiplex 23020841 Steinberg KM , et al. (2012)
- - 3_prime_UTR_variant Familial Maternal Multiplex 23020841 Steinberg KM , et al. (2012)
c.962T>C p.Val321Ala missense_variant Familial Maternal Simplex 23352163 Yu TW , et al. (2013)
c.916G>A p.Val306Met missense_variant Familial Maternal Simplex 23849776 Jiang YH , et al. (2013)
c.307delC p.Pro103fs frameshift_variant Unknown - Unknown 24126926 Kenny EM , et al. (2013)
c.1276G>A p.Gly426Ser missense_variant De novo - Simplex 24570023 Xu X , et al. (2014)
c.1849C>T p.Arg617Trp missense_variant Familial Maternal Extended multiplex 25167861 Redin C , et al. (2014)
c.583C>T p.Arg195Trp missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.1388G>A p.Trp463Ter stop_gained Familial Maternal Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1954A>G p.Thr652Ala missense_variant Unknown - Unknown 25549968 Li J , et al. (2015)
c.1286dupC;c.1346dupC;c.1406dupC p.Thr429fs;p.Thr449fs;p.Thr469fs frameshift_variant Familial Maternal Simplex 28263302 C Yuen RK , et al. (2017)
c.1286dupC;c.1346dupC;c.1406dupC p.Thr429fs;p.Thr449fs;p.Thr469fs frameshift_variant Familial Maternal Simplex 28263302 C Yuen RK , et al. (2017)
Common Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.-200-72A>G;c.-272A>G;c.-38-585A>G;c.47-72A>G;c.-116-72A>G G/A intron_variant - - - 21569590 Yu J , et al. (2011)
c.457+2188G>A;c.517+1489G>A;c.106+2188G>A;c.328+1489G>A;c.166+1489G>A A to G intron_variant - - - 21569590 Yu J , et al. (2011)
c.458-3490T>G;c.458-1753T>G;c.518-1753T>G;c.107-1753T>G;c.329-1753T>G;c.167-1753T>G G to T intron_variant - - - 21569590 Yu J , et al. (2011)
c.458-2809T>C;c.458-1072T>C;c.518-1072T>C;c.107-1072T>C;c.329-1072T>C;c.167-1072T>C C to T intron_variant - - - 21569590 Yu J , et al. (2011)
c.458-860A>G;c.517+818A>G;c.577+818A>G;c.166+818A>G;c.388+818A>G;c.226+818A>G G/A intron_variant - - - 21569590 Yu J , et al. (2011)
SFARI Gene score
2

Strong Candidate

A series of rare, deleterious variants have been reported in autism (Jamain et al., 2003 and Sanders et al., 2011; PMID: 21658581), and a gene expression study of lymphoblasts suggests reduced expression of the gene in ASD (Yasuda et al., 2011; PMID: 21615902). NLGN3 interacts with another ASD gene, NRXN1. This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015).

2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

07-01-2017
2

Initial score established: 2

Description

A series of rare, deleterious variants have been reported in autism (Jamain et al., 2003 and Sanders et al., 2011; PMID: 21658581), and a gene expression study of lymphoblasts suggests reduced expression of the gene in ASD (Yasuda et al., 2011; PMID: 21615902). NLGN3 interacts with another ASD gene, NRXN1. This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015).

CNVs associated with NLGN3(1 CNVs)
Xq13.1 14 Deletion-Duplication 24  /  41
Animal Models associated with NLGN3(28 Models)
NLGN3_10_cKO_D1-Cre Genetic
NLGN3_11_cKO_A2a-Cre Genetic
NLGN3_12_KI_R451C_D1-Cre Genetic
NLGN3_13_cKO_DS_Cre Genetic
NLGN3_14_cKO_NAc_Cre Genetic
NLGN3_15_cKO_D1-Cre_NAc_DIO-NL3 RESCUE-Genetic
NLGN3_16_KO_HM Genetic
NLGN3_17_KO_Purkinje RESCUE-Genetic
NLGN3_17_KO_Purkinje-Adult RESCUE-Genetic
NLGN3_18_CKO_HM Genetic
NLGN3_19_KO_HE Genetic
NLGN3_19_KO_HE_Pvalb-Cre RESCUE-Genetic
NLGN3_1_KI_R451C Genetic
NLGN3_1_KI_R451C_GEPH-GFP Genetic
NLGN3_1_KI_R451C_PSD95-GFP Genetic
NLGN3_20_KO_HE Genetic
NLGN3_22_KO_HM Genetic
NLGN3_23_KO_HM Genetic
NLGN3_24_KO_HT Genetic
NLGN3_25_KO_HT Genetic
NLGN3_2_KO Genetic
NLGN3_3_KI_R451C Genetic
NLGN3_4_KO Genetic
NLGN3_5_KO Genetic
NLGN3_6_KI_R451C Genetic
NLGN3_7_cKO_Nestin-Cre Genetic
NLGN3_8_cKO_L7-Cre Genetic
NLGN3_9_cKO_PV-Cre Genetic
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ACOT2 Human Protein Binding
ALPP CBS Human Protein Binding 250 P05187
C1QA Complement C1q subcomponent subunit A Human Protein Binding 712 P02745
CGB chorionic gonadotropin, beta polypeptide Human Protein Binding 1082 P01233
DPEP2 Dipeptidase 2 Human Protein Binding 64174 Q9H4A9
EBPL Emopamil-binding protein-like Human Protein Binding 84650 Q9BY08
GDF15 Growth/differentiation factor 15 Human Protein Binding 9518 Q99988
GPR175 Transmembrane protein adipocyte-associated 1 Human Protein Binding 131601 Q86W33
HID1 Protein HID1 Human Protein Binding 283987 Q8IV36
MIEN1 Migration and invasion enhancer 1 Human Protein Binding 84299 Q9BRT3
MT-CO2 Cytochrome c oxidase subunit 2 Human Protein Binding 4513 P00403
NLGN4Y Neuroligin-4, Y-linked Human Protein Binding 22829 Q8NFZ3
OR1F12 olfactory receptor, family 1, subfamily F, member 12 Human Protein Binding 442179 Q8NHA8
PLB1 Phospholipase B1, membrane-associated Human Protein Binding 151056 Q6P1J6
PLC4 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 Human Protein Binding 5332 Q15147
PSG1 Pregnancy-specific beta-1-glycoprotein 1 Human Protein Binding 5669 P11464
PSG11 pregnancy specific beta-1-glycoprotein 11 Human Protein Binding 5680 Q9UQ72
PSG3 Pregnancy-specific beta-1-glycoprotein 3 Human Protein Binding 5671 Q16557
PSG4 pregnancy specific beta-1-glycoprotein 4 Human Protein Binding 5672 Q00888
PSG5 Pregnancy-specific beta-1-glycoprotein 5 Human Protein Binding 5673 Q15238
RBM9 RNA binding protein fox-1 homolog 2 Human Protein Binding 9606 O43251
SPINT1 Kunitz-type protease inhibitor 1 Human Protein Binding 6692 O43278
TNNT3 Troponin T, fast skeletal muscle Human Protein Binding 7140 P45378
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