Human Gene Module / Chromosome 1 / ATP1A1

ATP1A1ATPase Na+/K+ transporting subunit alpha 1

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
4 / 8
Rare Variants / Common Variants
12 / 0
Aliases
ATP1A1, CMT2DD
Associated Syndromes
-
Chromosome Band
1p13.1
Associated Disorders
ASD
Relevance to Autism

Two de novo variants in the ATP1A1 gene (one loss-of-function, one damaging missense) were identified in ASD probands in whole-exome sequencing studies (De Rubeis et al., 2014; Iossifov et al., 2014). De novo missense variants in the ATP1A1 gene that resulted in loss of Na+,K+-ATPase function and abnormal cation permeabilities were identified in three unrelated individuals presenting with generalized seizures in infancy, severe hypomagnesemia, renal magnesium wasting, and developmental delay/intellectual disability; one of these three individuals was diagnosed with severe autism, while another was suspected of having autism spectrum disorder (Schlingmann et al., 2018).

Molecular Function

The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle.

External Links
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Human
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SFARI Genomic Platforms
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Reports related to ATP1A1 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent Recommendation Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability Schlingmann KP , et al. (2018) No ASD or autistic features
4 Support De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism Cappi C , et al. (2019) No -
5 Support Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability Chevarin M et al. (2020) No Marfanoid habitus
6 Support - Mitani T et al. (2021) No -
7 Support - Woodbury-Smith M et al. (2022) Yes -
8 Support - Zhou X et al. (2022) Yes -
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.390G>A p.Leu130%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1497G>A p.Ser499%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.12+719G>A - splice_site_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2707G>A p.Gly903Arg missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1166C>G p.Ala389Gly missense_variant De novo - Simplex 31771860 Cappi C , et al. (2019)
c.998C>G p.Pro333Arg missense_variant De novo - Simplex 32277047 Chevarin M et al. (2020)
c.1321C>G p.Pro441Ala missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.3007G>A p.Glu1003Lys missense_variant De novo - Multiplex 34582790 Mitani T et al. (2021)
c.2021C>G p.Thr674Ser missense_variant De novo - Multiplex 32277047 Chevarin M et al. (2020)
c.905T>G p.Leu302Arg missense_variant De novo - Simplex 30388404 Schlingmann KP , et al. (2018)
c.907G>C p.Gly303Arg missense_variant De novo - Simplex 30388404 Schlingmann KP , et al. (2018)
c.2576T>G p.Met859Arg missense_variant De novo - Simplex 30388404 Schlingmann KP , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Two de novo variants in the ATP1A1 gene (one loss-of-function, one damaging missense) were identified in ASD probands in whole-exome sequencing studies (De Rubeis et al., 2014; Iossifov et al., 2014). De novo missense variants in the ATP1A1 gene that resulted in loss of Na+,K+-ATPase function and abnormal cation permeabilities were identified in three unrelated individuals presenting with generalized seizures in infancy, severe hypomagnesemia, renal magnesium wasting, and developmental delay/intellectual disability; one of these three individuals was diagnosed with severe autism, while another was suspected of having autism spectrum disorder (Schlingmann et al., 2018).

Score Delta: Score remained at 2S

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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

Two de novo variants in the ATP1A1 gene (one loss-of-function, one damaging missense) were identified in ASD probands in whole-exome sequencing studies (De Rubeis et al., 2014; Iossifov et al., 2014). De novo missense variants in the ATP1A1 gene that resulted in loss of Na+,K+-ATPase function and abnormal cation permeabilities were identified in three unrelated individuals presenting with generalized seizures in infancy, severe hypomagnesemia, renal magnesium wasting, and developmental delay/intellectual disability; one of these three individuals was diagnosed with severe autism, while another was suspected of having autism spectrum disorder (Schlingmann et al., 2018).

4/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

Two de novo variants in the ATP1A1 gene (one loss-of-function, one damaging missense) were identified in ASD probands in whole-exome sequencing studies (De Rubeis et al., 2014; Iossifov et al., 2014). De novo missense variants in the ATP1A1 gene that resulted in loss of Na+,K+-ATPase function and abnormal cation permeabilities were identified in three unrelated individuals presenting with generalized seizures in infancy, severe hypomagnesemia, renal magnesium wasting, and developmental delay/intellectual disability; one of these three individuals was diagnosed with severe autism, while another was suspected of having autism spectrum disorder (Schlingmann et al., 2018).

Reports Added
[Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability2020]
1/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

Two de novo variants in the ATP1A1 gene (one loss-of-function, one damaging missense) were identified in ASD probands in whole-exome sequencing studies (De Rubeis et al., 2014; Iossifov et al., 2014). De novo missense variants in the ATP1A1 gene that resulted in loss of Na+,K+-ATPase function and abnormal cation permeabilities were identified in three unrelated individuals presenting with generalized seizures in infancy, severe hypomagnesemia, renal magnesium wasting, and developmental delay/intellectual disability; one of these three individuals was diagnosed with severe autism, while another was suspected of having autism spectrum disorder (Schlingmann et al., 2018).

Reports Added
[De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism.2019]
10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

Two de novo variants in the ATP1A1 gene (one loss-of-function, one damaging missense) were identified in ASD probands in whole-exome sequencing studies (De Rubeis et al., 2014; Iossifov et al., 2014). De novo missense variants in the ATP1A1 gene that resulted in loss of Na+,K+-ATPase function and abnormal cation permeabilities were identified in three unrelated individuals presenting with generalized seizures in infancy, severe hypomagnesemia, renal magnesium wasting, and developmental delay/intellectual disability; one of these three individuals was diagnosed with severe autism, while another was suspected of having autism spectrum disorder (Schlingmann et al., 2018).

Reports Added
[New Scoring Scheme]
10/1/2018
icon
4S

Increased from to 4S

Description

Two de novo variants in the ATP1A1 gene (one loss-of-function, one damaging missense) were identified in ASD probands in whole-exome sequencing studies (De Rubeis et al., 2014; Iossifov et al., 2014). De novo missense variants in the ATP1A1 gene that resulted in loss of Na+,K+-ATPase function and abnormal cation permeabilities were identified in three unrelated individuals presenting with generalized seizures in infancy, severe hypomagnesemia, renal magnesium wasting, and developmental delay/intellectual disability; one of these three individuals was diagnosed with severe autism, while another was suspected of having autism spectrum disorder (Schlingmann et al., 2018).

Krishnan Probability Score

Score 0.49354913016966

Ranking 4084/25841 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 0.99999385030547

Ranking 414/18225 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
Iossifov Probability Score

Score 0.884

Ranking 161/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.20321867286446

Ranking 113/18665 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 0.12914401497633

Ranking 5561/20870 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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