Human Gene Module / Chromosome 2 / SLC25A12

SLC25A12solute carrier family 25 (mitochondrial carrier, Aralar), member 12

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
15 / 24
Rare Variants / Common Variants
3 / 15
Aliases
SLC25A12, ARALAR,  ARALAR1
Associated Syndromes
-
Chromosome Band
2q31.1
Associated Disorders
ASD
Relevance to Autism

Several studies have found genetic association between the SLC25A12 gene and autism in SARC, AGRE and Irish population cohorts. However, several studies found no genetic association between the SLC25A12 gene and autism in IMGSAC, Chinese Han, Caucasian-American and Portuguese population cohorts.

Molecular Function

The encoded protein has solute:cation symporter activity.

SFARI Genomic Platforms
Reports related to SLC25A12 (24 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism Ramoz N , et al. (2004) Yes -
2 Negative Association SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample Blasi F , et al. (2005) Yes -
3 Positive Association Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31 Segurado R , et al. (2005) Yes -
4 Recent Recommendation Essential role of aralar in the transduction of small Ca2+ signals to neuronal mitochondria Pardo B , et al. (2005) No -
5 Negative Association Lack of association between autism and SLC25A12 Rabionet R , et al. (2006) Yes -
6 Negative Association Brief report: High frequency of biochemical markers for mitochondrial dysfunction in autism: no association with the mitochondrial aspartate/glutamate carrier SLC25A12 gene Correia C , et al. (2006) Yes -
7 Recent Recommendation Role of aralar, the mitochondrial transporter of aspartate-glutamate, in brain N-acetylaspartate formation and Ca(2+) signaling in neuronal mitochondria Satrstegui J , et al. (2007) No -
8 Positive Association Autism-related routines and rituals associated with a mitochondrial aspartate/glutamate carrier SLC25A12 polymorphism Silverman JM , et al. (2007) Yes Restricted and repetitive behaviors
9 Recent Recommendation SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects Lepagnol-Bestel AM , et al. (2008) No -
10 Positive Association An analysis of candidate autism loci on chromosome 2q24-q33: evidence for association to the STK39 gene Ramoz N , et al. (2008) Yes -
11 Positive Association Mitochondrial aspartate/glutamate carrier SLC25A12 gene is associated with autism Turunen JA , et al. (2009) Yes -
12 Negative Association Association study of the SLC25A12 gene and autism in Han Chinese in Taiwan Chien WH , et al. (2009) Yes -
13 Positive Association A quantitative association study of SLC25A12 and restricted repetitive behavior traits in autism spectrum disorders Kim SJ , et al. (2011) No -
14 Negative Association The association of rs4307059 and rs35678 markers with autism spectrum disorders is replicated in Italian families Prandini P , et al. (2012) Yes -
15 Support Brain region-specific altered expression and association of mitochondria-related genes in autism Anitha A , et al. (2012) Yes -
16 Positive Association Single nucleotide polymorphism rs6716901 in SLC25A12 gene is associated with Asperger syndrome Durdiakov J , et al. (2014) Yes Asperger syndrome
17 Positive Association Mitochondrial Aspartate/Glutamate Carrier SLC25A12 and Autism Spectrum Disorder: a Meta-Analysis Aoki Y and Cortese S (2015) Yes -
18 Positive Association Association between genetic variants in SLC25A12 and risk of autism spectrum disorders: An integrated meta-analysis Liu J , et al. (2015) Yes -
19 Recent Recommendation In Vivo Detection of Mitochondrial Dysfunction Induced by Clinical Drugs and Disease-Associated Genes Using a Novel Dye ZMJ214 in Zebrafish Sasagawa S , et al. (2015) No -
20 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
21 Support Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits Kanellopoulos AK et al. (2020) No -
22 Support - Brunet T et al. (2021) No -
23 Support - Mir A et al. (2021) No -
24 Highly Cited Molecular cloning of Aralar, a new member of the mitochondrial carrier superfamily that binds calcium and is present in human muscle and brain del Arco A and Satrstegui J (1998) No -
Rare Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - Unknown 33619735 Brunet T et al. (2021)
c.832T>C p.Tyr278His missense_variant Familial Both parents - 34797406 Mir A et al. (2021)
c.2016del p.Ala673GlnfsTer19 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.931-1741C>T;c.880-1741C>T;c.610-1741C>T - intron_variant - - - 24679184 Durdiakov J , et al. (2014)
c.845+293A>G;c.794+293A>G;c.524+293A>G;c.572+293A>G - intron_variant - - - 21609426 Kim SJ , et al. (2011)
c.210-21A>G;c.159-21A>G;c.5-11462A>G - intron_variant - - - 25921325 Liu J , et al. (2015)
c.210-21A>G;c.159-21A>G;c.5-11462A>G - intron_variant - - - 21609426 Kim SJ , et al. (2011)
c.1745-58A>G;c.1694-58A>G;c.1424-58A>G - intron_variant - - - 25921325 Liu J , et al. (2015)
c.210-21A>G;c.159-21A>G;c.5-11462A>G - intron_variant - - - 15056512 Ramoz N , et al. (2004)
c.210-21A>G;c.159-21A>G;c.5-11462A>G - intron_variant - - - 18348195 Ramoz N , et al. (2008)
c.1745-58A>G;c.1694-58A>G;c.1424-58A>G - intron_variant - - - 21609426 Kim SJ , et al. (2011)
c.1745-58A>G;c.1694-58A>G;c.1424-58A>G - intron_variant - - - 15056512 Ramoz N , et al. (2004)
c.210-21A>G;c.159-21A>G;c.5-11462A>G - intron_variant - - - 16263864 Segurado R , et al. (2005)
c.210-21A>G;c.159-21A>G;c.5-11462A>G - intron_variant - - - 25663199 Aoki Y and Cortese S (2015)
c.1745-58A>G;c.1694-58A>G;c.1424-58A>G - intron_variant - - - 16263864 Segurado R , et al. (2005)
c.1745-58A>G;c.1694-58A>G;c.1424-58A>G - intron_variant - - - 19360665 Turunen JA , et al. (2009)
c.210-21A>G;c.159-21A>G;c.5-11462A>G - intron_variant - - - 17894412 Silverman JM , et al. (2007)
c.1745-58A>G;c.1694-58A>G;c.1424-58A>G - intron_variant - - - 25663199 Aoki Y and Cortese S (2015)
SFARI Gene score
2

Strong Candidate

Multiple but inconsistent associations reported.

Score Delta: Score remained at 2

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

Multiple but inconsistent associations reported.

1/1/2021
3
icon
3

Decreased from 3 to 3

Description

Multiple but inconsistent associations reported.

4/1/2020
3
icon
3

Decreased from 3 to 3

Description

Multiple but inconsistent associations reported.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Multiple but inconsistent associations reported.

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Multiple but inconsistent associations reported.

7/1/2017
4
icon
4

Decreased from 4 to 4

Description

Multiple but inconsistent associations reported.

1/1/2016
4
icon
4

Decreased from 4 to 4

Description

Multiple but inconsistent associations reported.

Reports Added
[SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample.2005] [Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31.2005] [Lack of association between autism and SLC25A12.2006] [Brief report: High frequency of biochemical markers for mitochondrial dysfunction in autism: no association with the mitochondrial aspartate/glutam...2006] [Autism-related routines and rituals associated with a mitochondrial aspartate/glutamate carrier SLC25A12 polymorphism.2007] [Association study of the SLC25A12 gene and autism in Han Chinese in Taiwan.2009] [The association of rs4307059 and rs35678 markers with autism spectrum disorders is replicated in Italian families.2012] [Brain region-specific altered expression and association of mitochondria-related genes in autism.2012] [Single nucleotide polymorphism rs6716901 in SLC25A12 gene is associated with Asperger syndrome.2014] [Mitochondrial Aspartate/Glutamate Carrier SLC25A12 and Autism Spectrum Disorder: a Meta-Analysis.2015] [An analysis of candidate autism loci on chromosome 2q24-q33: evidence for association to the STK39 gene.2008] [Mitochondrial aspartate/glutamate carrier SLC25A12 gene is associated with autism.2009] [Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism.2004] [Molecular cloning of Aralar, a new member of the mitochondrial carrier superfamily that binds calcium and is present in human muscle and brain.1998] [Essential role of aralar in the transduction of small Ca2 signals to neuronal mitochondria.2005] [Role of aralar, the mitochondrial transporter of aspartate-glutamate, in brain N-acetylaspartate formation and Ca(2) signaling in neuronal mitocho...2007] [SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects.2008] [Association between genetic variants in SLC25A12 and risk of autism spectrum disorders: An integrated meta-analysis.2015] [In Vivo Detection of Mitochondrial Dysfunction Induced by Clinical Drugs and Disease-Associated Genes Using a Novel Dye ZMJ214 in Zebrafish.2015]
4/1/2015
4
icon
4

Decreased from 4 to 4

Description

Multiple but inconsistent associations reported.

7/1/2014
No data
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4

Increased from No data to 4

Description

Multiple but inconsistent associations reported.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Multiple but inconsistent associations reported.

Krishnan Probability Score

Score 0.44738237821326

Ranking 12528/25841 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.
ExAC Score

Score 0.88705048177734

Ranking 3332/18225 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
Sanders TADA Score

Score 0.93605896904102

Ranking 13074/18665 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).
Larsen Cumulative Evidence Score

Score 8

Ranking 235/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.15475597886494

Ranking 5084/20870 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.
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