Human Gene Module / Chromosome 3 / CX3CR1

CX3CR1Chemokine (C-X3-C motif) receptor 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 4
Rare Variants / Common Variants
6 / 1
Aliases
CX3CR1, CCRL1,  CMKBRL1,  CMKDR1,  GPR13,  GPRV28,  V28
Associated Syndromes
-
Chromosome Band
3p22.2
Associated Disorders
-
Relevance to Autism

Mice lacking the chemokine receptor Cx3cr1 exhibit a transient reduction of microglia during the early postnatal period and a consequent deficit in synaptic pruning, which in turn is associated with weak synaptic transmission, decreased functional brain connectivity, deficits in social interaction and increased repetitive-behavior phenotypes that have been previously associated with autism and other neurodevelopmental and neuropsychiatric disorders (Zhan et al., 2014). Targeted resequencing of the CX3CR1 gene in 370 Japanese schizophrenia and 192 ASD patients identified several rare missense variants, including a missense variant (p.Ala55Thr) in one ASD proband and one schizophrenia proband that inhibited fractakline-induced phosporylation of Akt in transfected cells (Ishizuka et al., 2017). Furthermore, an independent genetic association study in a sample consisting of 2653 Japanese schizophrenia cases, 574 Japanese ASD cases, and 3827 ethnically-matched controls demonstrated that the CX3CR1 p.Ala55Thr missense variant associated with both ASD (Odds ratio 13.3 [1.04-Inf], P=0.0047) and schizophrenia (Odds ratio 7.2 [1.04-Inf], P=0.045).

Molecular Function

Receptor for the CX3C chemokine fractalkine and mediates both its adhesive and migratory functions. Expressed in lymphoid and neural tissues.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CX3CR1 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Altered gene expression and function of peripheral blood natural killer cells in children with autism Enstrom AM , et al. (2008) Yes -
2 Primary Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior Zhan Y , et al. (2014) No -
3 Recent Recommendation Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders Ishizuka K , et al. (2017) Yes -
4 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.163G>A p.Ala55Thr missense_variant Unknown - Unknown 28763059 Ishizuka K , et al. (2017)
c.335G>C p.Gly112Ala missense_variant Unknown - Unknown 28763059 Ishizuka K , et al. (2017)
c.414G>T p.Met138Ile missense_variant Unknown - Unknown 28763059 Ishizuka K , et al. (2017)
c.163G>A p.Ala55Thr missense_variant Familial Paternal Simplex 28763059 Ishizuka K , et al. (2017)
c.462G>A p.Trp154Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.335G>C p.Gly112Ala missense_variant Familial Maternal Simplex 28763059 Ishizuka K , et al. (2017)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.163G>A p.Ala55Thr missense_variant - - - 28763059 Ishizuka K , et al. (2017)
SFARI Gene score
2

Strong Candidate

Mice lacking the chemokine receptor Cx3cr1 exhibit a transient reduction of microglia during the early postnatal period and a consequent deficit in synaptic pruning, which in turn is associated with weak synaptic transmission, decreased functional brain connectivity, deficits in social interaction and increased repetitive-behavior phenotypes that have been previously associated with autism and other neurodevelopmental and neuropsychiatric disorders (PMID 24487234). A gene expression screen and cellular functional analysis on peripheral blood obtained from 52 children with ASD and 27 typically developing control children enrolled in the case-control CHARGE study found a 1.8-fold change in CX3CR1 expression (PMID 18762240). Targeted resequencing of the CX3CR1 gene in 370 Japanese schizophrenia and 192 ASD patients identified several rare missense variants, including a missense variant (p.Ala55Thr) in one ASD proband and one schizophrenia proband that inhibited fractakline-induced phosporylation of Akt in transfected cells (Ishizuka et al., 2017). Furthermore, an independent genetic association study in a sample consisting of 2653 Japanese schizophrenia cases, 574 Japanese ASD cases, and 3827 ethnically-matched controls demonstrated that the CX3CR1 p.Ala55Thr missense variant associated with both ASD (Odds ratio 13.3 [1.04-Inf], P=0.0047) and schizophrenia (Odds ratio 7.2 [1.04-Inf], P=0.045).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Mice lacking the chemokine receptor Cx3cr1 exhibit a transient reduction of microglia during the early postnatal period and a consequent deficit in synaptic pruning, which in turn is associated with weak synaptic transmission, decreased functional brain connectivity, deficits in social interaction and increased repetitive-behavior phenotypes that have been previously associated with autism and other neurodevelopmental and neuropsychiatric disorders (PMID 24487234). A gene expression screen and cellular functional analysis on peripheral blood obtained from 52 children with ASD and 27 typically developing control children enrolled in the case-control CHARGE study found a 1.8-fold change in CX3CR1 expression (PMID 18762240). Targeted resequencing of the CX3CR1 gene in 370 Japanese schizophrenia and 192 ASD patients identified several rare missense variants, including a missense variant (p.Ala55Thr) in one ASD proband and one schizophrenia proband that inhibited fractakline-induced phosporylation of Akt in transfected cells (Ishizuka et al., 2017). Furthermore, an independent genetic association study in a sample consisting of 2653 Japanese schizophrenia cases, 574 Japanese ASD cases, and 3827 ethnically-matched controls demonstrated that the CX3CR1 p.Ala55Thr missense variant associated with both ASD (Odds ratio 13.3 [1.04-Inf], P=0.0047) and schizophrenia (Odds ratio 7.2 [1.04-Inf], P=0.045).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Mice lacking the chemokine receptor Cx3cr1 exhibit a transient reduction of microglia during the early postnatal period and a consequent deficit in synaptic pruning, which in turn is associated with weak synaptic transmission, decreased functional brain connectivity, deficits in social interaction and increased repetitive-behavior phenotypes that have been previously associated with autism and other neurodevelopmental and neuropsychiatric disorders (PMID 24487234). A gene expression screen and cellular functional analysis on peripheral blood obtained from 52 children with ASD and 27 typically developing control children enrolled in the case-control CHARGE study found a 1.8-fold change in CX3CR1 expression (PMID 18762240). Targeted resequencing of the CX3CR1 gene in 370 Japanese schizophrenia and 192 ASD patients identified several rare missense variants, including a missense variant (p.Ala55Thr) in one ASD proband and one schizophrenia proband that inhibited fractakline-induced phosporylation of Akt in transfected cells (Ishizuka et al., 2017). Furthermore, an independent genetic association study in a sample consisting of 2653 Japanese schizophrenia cases, 574 Japanese ASD cases, and 3827 ethnically-matched controls demonstrated that the CX3CR1 p.Ala55Thr missense variant associated with both ASD (Odds ratio 13.3 [1.04-Inf], P=0.0047) and schizophrenia (Odds ratio 7.2 [1.04-Inf], P=0.045).

Reports Added
[New Scoring Scheme]
7/1/2017
5
icon
4

Decreased from 5 to 4

Description

Mice lacking the chemokine receptor Cx3cr1 exhibit a transient reduction of microglia during the early postnatal period and a consequent deficit in synaptic pruning, which in turn is associated with weak synaptic transmission, decreased functional brain connectivity, deficits in social interaction and increased repetitive-behavior phenotypes that have been previously associated with autism and other neurodevelopmental and neuropsychiatric disorders (PMID 24487234). A gene expression screen and cellular functional analysis on peripheral blood obtained from 52 children with ASD and 27 typically developing control children enrolled in the case-control CHARGE study found a 1.8-fold change in CX3CR1 expression (PMID 18762240). Targeted resequencing of the CX3CR1 gene in 370 Japanese schizophrenia and 192 ASD patients identified several rare missense variants, including a missense variant (p.Ala55Thr) in one ASD proband and one schizophrenia proband that inhibited fractakline-induced phosporylation of Akt in transfected cells (Ishizuka et al., 2017). Furthermore, an independent genetic association study in a sample consisting of 2653 Japanese schizophrenia cases, 574 Japanese ASD cases, and 3827 ethnically-matched controls demonstrated that the CX3CR1 p.Ala55Thr missense variant associated with both ASD (Odds ratio 13.3 [1.04-Inf], P=0.0047) and schizophrenia (Odds ratio 7.2 [1.04-Inf], P=0.045).

Reports Added
[Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders.2017]
7/1/2015
icon
5

Increased from to 5

Description

Mice lacking the chemokine receptor Cx3cr1 exhibit a transient reduction of microglia during the early postnatal period and a consequent deficit in synaptic pruning, which in turn is associated with weak synaptic transmission, decreased functional brain connectivity, deficits in social interaction and increased repetitive-behavior phenotypes that have been previously associated with autism and other neurodevelopmental and neuropsychiatric disorders (PMID 24487234). A gene expression screen and cellular functional analysis on peripheral blood obtained from 52 children with ASD and 27 typically developing control children enrolled in the case-control CHARGE study found a 1.8-fold change in CX3CR1 expression (PMID 18762240).

Krishnan Probability Score

Score 0.48186565211212

Ranking 7884/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.10729164124876

Ranking 7780/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.91998211101744

Ranking 9100/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.30959936003685

Ranking 2596/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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