Human Gene Module / Chromosome 16 / MAPK3

MAPK3mitogen-activated protein kinase 3

Score
4
Minimal Evidence Criteria 4.1
Autism Reports / Total Reports
2 / 4
Rare Variants / Common Variants
4 / 0
Aliases
MAPK3, ERK1,  HS44KDAP,  HUMKER1A,  MGC20180,  P44ERK1,  P44MAPK,  PRKM3
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
16p11.2
Associated Disorders
-
Relevance to Autism

Rare mutations in the MAPK3 gene have been identified with ASD (Schaaf et al., 2011).

Molecular Function

The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act in a signaling cascade that regulates various cellular processes such as proliferation, differentiation, and cell cycle progression in response to a variety of extracellular signals. This kinase is activated by upstream kinases, resulting in its translocation to the nucleus where it phosphorylates nuclear targets. Alternatively spliced transcript variants encoding different protein isoforms have been described.

Reports related to MAPK3 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders. Schaaf CP , et al. (2011) Yes -
2 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
3 Recent Recommendation MAPK3 at the Autism-Linked Human 16p11.2 Locus Influences Precise Synaptic Target Selection at Drosophila Larval Neuromuscular Junctions. Park SM , et al. (2017) No -
4 Recent Recommendation Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Gusev A , et al. (2018) No -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.934C>T;c.292C>T p.Pro312Ser;p.Pro98Ser missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.331A>C p.Thr111Pro missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.833G>A p.Arg278Gln missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1070C>T p.Thr357Met missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
4

Minimal Evidence

4

Score Delta: Score remained at 4.4

4

Minimal Evidence

See all Category 4 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as 'acc" in the score cards) could also boost a gene from category 4 to 3.

1/1/2017
4
icon
4

Score remained at 4

Description

Rare mutations in the MAPK3 gene have been identified with ASD (Schaaf et al., 2011)

1/1/2016
4
icon
4

Score remained at 4

Description

Rare mutations in the MAPK3 gene have been identified with ASD (Schaaf et al., 2011)

7/1/2014
No data
icon
4

Increased from No data to 4

Description

Rare mutations in the MAPK3 gene have been identified with ASD (Schaaf et al., 2011)

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Rare mutations in the MAPK3 gene have been identified with ASD (Schaaf et al., 2011)

Krishnan Probability Score

Score 0.49049627161556

Ranking 6096/25841 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 0.40969232837464

Ranking 5916/18225 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 0.70036393666162

Ranking 1159/18665 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 6

Ranking 260/461 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 -0.34946035456306

Ranking 17823/20870 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.
CNVs associated with MAPK3(1 CNVs)
16p11.2 103 Deletion-Duplication 166  /  1531
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CPLX4 Complexin-4 Human Protein Binding 339302 Q7Z7G2
DHPS deoxyhypusine synthase Human Protein Binding 1725 P49366
NAB2 NGFI-A binding protein 2 (EGR1 binding protein 2) Human Protein Binding 4665 Q15742
RPS6KA6 Ribosomal protein S6 kinase alpha-6 Human Protein Binding 27330 Q9UK32
ZDHHC11 zinc finger, DHHC-type containing 11 Human Protein Binding 79844 Q9H8X9
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