Human Gene Module / Chromosome 16 / MAPK3

MAPK3mitogen-activated protein kinase 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
11 / 0
Aliases
MAPK3, ERK1,  HS44KDAP,  HUMKER1A,  MGC20180,  P44ERK1,  P44MAPK,  PRKM3
Associated Syndromes
-
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.

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Reports related to MAPK3 (6 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 -
5 Negative Association Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans Wong WR , et al. (2019) Yes -
6 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.190C>T p.Arg64Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.202G>C p.Val68Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.421G>A p.Asp141Asn missense_variant De novo - - 33004838 Wang T et al. (2020)
c.679G>A p.Asp227Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.802G>A p.Asp268Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1139A>G p.Ter380TrpextTer24 stop_lost Unknown - - 33004838 Wang T et al. (2020)
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)
c.361G>A p.Val121Met missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.331A>C p.Thr111Pro missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.934C>T;c.292C>T p.Pro312Ser;p.Pro98Ser missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

MAPK3 resides within the 16p11.2 microdeletion/microduplication region; deletions and duplications in this region are strongly associated with neurodevelopmental disorders, including ASD. Missense variants in the MAPK3 gene were identified in ASD probands in Schaaf et al., 2011 and De Rubeis et al., 2014. Park et al., 2017 demonstrated that a mutation in the Drospholia homolog of MAPK3 caused ectopic innervation and abnormal defasciculation of axonal branches at larval neuromuscular junctions. Transcriptome-wide association study (TWAS) of schizophrenia and chromatic activity in Gusev et al., 2018 found that total expression of MAPK3 in CMC brain data was associated with schizophrenia (P=1.3E-06), as well as two chromatin peaks near the TSS: H3K27ac (P=7.0E-06) and RPB2 (P=1.0E-11); furthermore, suppression of endogeneous mapk3 was able to rescue the microcephaly and neuronal-proliferation phenotypes induced by overexpression of wild-type KCTD13 in Drosophila.

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

MAPK3 resides within the 16p11.2 microdeletion/microduplication region; deletions and duplications in this region are strongly associated with neurodevelopmental disorders, including ASD. Missense variants in the MAPK3 gene were identified in ASD probands in Schaaf et al., 2011 and De Rubeis et al., 2014. Park et al., 2017 demonstrated that a mutation in the Drospholia homolog of MAPK3 caused ectopic innervation and abnormal defasciculation of axonal branches at larval neuromuscular junctions. Transcriptome-wide association study (TWAS) of schizophrenia and chromatic activity in Gusev et al., 2018 found that total expression of MAPK3 in CMC brain data was associated with schizophrenia (P=1.3E-06), as well as two chromatin peaks near the TSS: H3K27ac (P=7.0E-06) and RPB2 (P=1.0E-11); furthermore, suppression of endogeneous mapk3 was able to rescue the microcephaly and neuronal-proliferation phenotypes induced by overexpression of wild-type KCTD13 in Drosophila.

10/1/2020
3
icon
3

Decreased from 3 to 3

Description

MAPK3 resides within the 16p11.2 microdeletion/microduplication region; deletions and duplications in this region are strongly associated with neurodevelopmental disorders, including ASD. Missense variants in the MAPK3 gene were identified in ASD probands in Schaaf et al., 2011 and De Rubeis et al., 2014. Park et al., 2017 demonstrated that a mutation in the Drospholia homolog of MAPK3 caused ectopic innervation and abnormal defasciculation of axonal branches at larval neuromuscular junctions. Transcriptome-wide association study (TWAS) of schizophrenia and chromatic activity in Gusev et al., 2018 found that total expression of MAPK3 in CMC brain data was associated with schizophrenia (P=1.3E-06), as well as two chromatin peaks near the TSS: H3K27ac (P=7.0E-06) and RPB2 (P=1.0E-11); furthermore, suppression of endogeneous mapk3 was able to rescue the microcephaly and neuronal-proliferation phenotypes induced by overexpression of wild-type KCTD13 in Drosophila.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

MAPK3 resides within the 16p11.2 microdeletion/microduplication region; deletions and duplications in this region are strongly associated with neurodevelopmental disorders, including ASD. Missense variants in the MAPK3 gene were identified in ASD probands in Schaaf et al., 2011 and De Rubeis et al., 2014. Park et al., 2017 demonstrated that a mutation in the Drospholia homolog of MAPK3 caused ectopic innervation and abnormal defasciculation of axonal branches at larval neuromuscular junctions. Transcriptome-wide association study (TWAS) of schizophrenia and chromatic activity in Gusev et al., 2018 found that total expression of MAPK3 in CMC brain data was associated with schizophrenia (P=1.3E-06), as well as two chromatin peaks near the TSS: H3K27ac (P=7.0E-06) and RPB2 (P=1.0E-11); furthermore, suppression of endogeneous mapk3 was able to rescue the microcephaly and neuronal-proliferation phenotypes induced by overexpression of wild-type KCTD13 in Drosophila.

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

Decreased from 4 to 4

Description

MAPK3 resides within the 16p11.2 microdeletion/microduplication region; deletions and duplications in this region are strongly associated with neurodevelopmental disorders, including ASD. Missense variants in the MAPK3 gene were identified in ASD probands in Schaaf et al., 2011 and De Rubeis et al., 2014. Park et al., 2017 demonstrated that a mutation in the Drospholia homolog of MAPK3 caused ectopic innervation and abnormal defasciculation of axonal branches at larval neuromuscular junctions. Transcriptome-wide association study (TWAS) of schizophrenia and chromatic activity in Gusev et al., 2018 found that total expression of MAPK3 in CMC brain data was associated with schizophrenia (P=1.3E-06), as well as two chromatin peaks near the TSS: H3K27ac (P=7.0E-06) and RPB2 (P=1.0E-11); furthermore, suppression of endogeneous mapk3 was able to rescue the microcephaly and neuronal-proliferation phenotypes induced by overexpression of wild-type KCTD13 in Drosophila.

Reports Added
[Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans.2019]
1/1/2017
4
icon
4

Decreased from 4 to 4

Description

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

Reports Added
[MAPK3 at the Autism-Linked Human 16p11.2 Locus Influences Precise Synaptic Target Selection at Drosophila Larval Neuromuscular Junctions.2017]
1/1/2016
4
icon
4

Decreased from 4 to 4

Description

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

Reports Added
[Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
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.
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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.
Original Source
CNVs associated with MAPK3(1 CNVs)
Sort By:
16p11.2 145 Deletion-Duplication 212  /  1657
Interactome
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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