Human Gene Module / Chromosome 1 / MARK1

MARK1microtubule affinity regulating kinase 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 12
Rare Variants / Common Variants
5 / 8
Aliases
MARK1, MARK,  KIAA1477,  MGC126512,  MGC126513,  MARK1
Associated Syndromes
-
Chromosome Band
1q41
Associated Disorders
-
Relevance to Autism

Several SNPs within the MARK1 gene were significantly associated with ASDs by transmission disequilibrium tests in a family-based association study of multiplex ASD families. The ASD-associated SNP rs12410279 was found to modulate the level of MARK1 transcription. Furthermore, MARK1 was overexpressed in the prefrontal cortex of patients with autism and causes changes in the function of cortical dendrites (Maussion et al., 2008).

Molecular Function

Serine/threonine-protein kinase involved in cell polarity and microtubule dynamics regulation. Phosphorylates DCX, MAP2, MAP4 and MAPT/TAU. Involved in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MARK1 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Structural variations in the catalytic and ubiquitin-associated domains of microtubule-associated protein/microtubule affinity regulating kinase (MARK) 1 and MARK2 Marx A , et al. (2006) No -
2 Recent Recommendation Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity Saadat I , et al. (2007) No -
3 Recent Recommendation Genetic defects underlying Peutz-Jeghers syndrome (PJS) and exclusion of the polarity-associated MARK/Par1 gene family as potential PJS candidates de Leng WW , et al. (2007) No -
4 Primary Convergent evidence identifying MAP/microtubule affinity-regulating kinase 1 (MARK1) as a susceptibility gene for autism Maussion G , et al. (2008) Yes -
5 Recent Recommendation Interactions of MAP/microtubule affinity regulating kinases with the adaptor complex AP-2 of clathrin-coated vesicles Schmitt-Ulms G , et al. (2009) No -
6 Support De novo mutations in schizophrenia implicate synaptic networks Fromer M , et al. (2014) Yes -
7 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
8 Recent Recommendation De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia Takata A , et al. (2016) No -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Wang J et al. (2023) Yes -
11 Highly Cited Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262 Drewes G , et al. (1995) No -
12 Highly Cited MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption Drewes G , et al. (1997) No -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2091G>A p.Lys697%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.2094G>A p.Pro698= synonymous_variant De novo - - 24463507 Fromer M , et al. (2014)
c.1511C>T p.Thr504Ile missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.2168_2169del p.Arg723GlnfsTer7 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.692A>G p.Lys231Arg missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1736+31A>G;c.1670+31A>G;c.1472+31A>G;c.1244+31A>G - intron_variant - - - 18492799 Maussion G , et al. (2008)
c.2037-1164C>T;c.1989-1164C>T;c.1923-1164C>T;c.2034-1164C>T;c.1992-1164C>T;c.1773-1164C>T;c.1545-116 C/T intron_variant - - - 18492799 Maussion G , et al. (2008)
- A/G intergenic_variant - - - 18492799 Maussion G , et al. (2008)
- A/T 5KB_upstream_variant - - - 18492799 Maussion G , et al. (2008)
c.52-23499A>G - intron_variant - - - 18492799 Maussion G , et al. (2008)
c.51+18345T>C C/T intron_variant - - - 18492799 Maussion G , et al. (2008)
c.309+8064C>T;c.-94-4722C>T - intron_variant - - - 18492799 Maussion G , et al. (2008)
c.309+7473T>C;c.-94-5313T>C C/T intron_variant - - - 18492799 Maussion G , et al. (2008)
SFARI Gene score
2

Strong Candidate

A TDT in 276 AGRE families using 126 SNPs across the 1q41 interval suggested association with SNPs and haplotypes in the MARK1 gene. One associated SNP (rs12410279) was observed to modulate transcription of MARK1. The gene is overexpressed in the prefrontal cortex (BA46) but not in cerebellar granule cells, in brain tissues from patients. Overexpression and silencing of MARK1 resulted in significantly shorter dendrite length in mouse neocortical neurons and modified dendritic transport speed (Maussion G et al.).

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

A TDT in 276 AGRE families using 126 SNPs across the 1q41 interval suggested association with SNPs and haplotypes in the MARK1 gene. One associated SNP (rs12410279) was observed to modulate transcription of MARK1. The gene is overexpressed in the prefrontal cortex (BA46) but not in cerebellar granule cells, in brain tissues from patients. Overexpression and silencing of MARK1 resulted in significantly shorter dendrite length in mouse neocortical neurons and modified dendritic transport speed (Maussion G et al.).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A TDT in 276 AGRE families using 126 SNPs across the 1q41 interval suggested association with SNPs and haplotypes in the MARK1 gene. One associated SNP (rs12410279) was observed to modulate transcription of MARK1. The gene is overexpressed in the prefrontal cortex (BA46) but not in cerebellar granule cells, in brain tissues from patients. Overexpression and silencing of MARK1 resulted in significantly shorter dendrite length in mouse neocortical neurons and modified dendritic transport speed (Maussion G et al.).

Reports Added
[New Scoring Scheme]
4/1/2016
4
icon
4

Decreased from 4 to 4

Description

A TDT in 276 AGRE families using 126 SNPs across the 1q41 interval suggested association with SNPs and haplotypes in the MARK1 gene. One associated SNP (rs12410279) was observed to modulate transcription of MARK1. The gene is overexpressed in the prefrontal cortex (BA46) but not in cerebellar granule cells, in brain tissues from patients. Overexpression and silencing of MARK1 resulted in significantly shorter dendrite length in mouse neocortical neurons and modified dendritic transport speed (Maussion G et al.).

Reports Added
[Convergent evidence identifying MAP/microtubule affinity-regulating kinase 1 (MARK1) as a susceptibility gene for autism.2008] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interaction...1995] [MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption.1997] [Structural variations in the catalytic and ubiquitin-associated domains of microtubule-associated protein/microtubule affinity regulating kinase (M...2006] [Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity.2007] [Genetic defects underlying Peutz-Jeghers syndrome (PJS) and exclusion of the polarity-associated MARK/Par1 gene family as potential PJS candidates.2007] [Interactions of MAP/microtubule affinity regulating kinases with the adaptor complex AP-2 of clathrin-coated vesicles.2009] [De novo mutations in schizophrenia implicate synaptic networks.2014] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016]
1/1/2015
4
icon
4

Decreased from 4 to 4

Description

A TDT in 276 AGRE families using 126 SNPs across the 1q41 interval suggested association with SNPs and haplotypes in the MARK1 gene. One associated SNP (rs12410279) was observed to modulate transcription of MARK1. The gene is overexpressed in the prefrontal cortex (BA46) but not in cerebellar granule cells, in brain tissues from patients. Overexpression and silencing of MARK1 resulted in significantly shorter dendrite length in mouse neocortical neurons and modified dendritic transport speed (Maussion G et al.).

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

A TDT in 276 AGRE families using 126 SNPs across the 1q41 interval suggested association with SNPs and haplotypes in the MARK1 gene. One associated SNP (rs12410279) was observed to modulate transcription of MARK1. The gene is overexpressed in the prefrontal cortex (BA46) but not in cerebellar granule cells, in brain tissues from patients. Overexpression and silencing of MARK1 resulted in significantly shorter dendrite length in mouse neocortical neurons and modified dendritic transport speed (Maussion G et al.).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

A TDT in 276 AGRE families using 126 SNPs across the 1q41 interval suggested association with SNPs and haplotypes in the MARK1 gene. One associated SNP (rs12410279) was observed to modulate transcription of MARK1. The gene is overexpressed in the prefrontal cortex (BA46) but not in cerebellar granule cells, in brain tissues from patients. Overexpression and silencing of MARK1 resulted in significantly shorter dendrite length in mouse neocortical neurons and modified dendritic transport speed (Maussion G et al.).

Krishnan Probability Score

Score 0.60691404905121

Ranking 308/25841 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 0.99082567584205

Ranking 1771/18225 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 0.93825954052177

Ranking 13802/18665 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 24

Ranking 82/461 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 0.29137488659915

Ranking 2865/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CDH19 CDH19 protein Human Protein Binding Q96KY9
GJA5 gap junction protein, alpha 5, 40kDa Human Protein Binding 2702 P36382
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