Human Gene Module / Chromosome 1 / KCNJ10

KCNJ10potassium voltage-gated channel subfamily J member 10

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 14
Rare Variants / Common Variants
13 / 2
Aliases
KCNJ10, BIRK-10,  KCNJ13-PEN,  KIR1.2,  KIR4.1,  SESAME
Associated Syndromes
SESAME syndrome, Fragile X syndrome
Chromosome Band
1q23.2
Associated Disorders
ID, EPS
Relevance to Autism

Rare mutations in the KCNJ10 gene have been identified with autism (Sicca et al., 2011). In particular, that study found two non-synonymous SNPs (P18Q and V84M) in unrelated individuals with a seizure disorder who also have ASD and ID. Both of these mutations were shown to be functional in heterologous systems. In addition, genetic association has been found between KCNJ10 and seizure susceptibility in patients with epilepsy (Buono et al., 2004).

Molecular Function

This gene encodes a member of the inward rectifier-type potassium channel family, characterized by having a greater tendency to allow potassium to flow into, rather than out of, a cell. The encoded protein may form a heterodimer with another potassium channel protein and may be responsible for the potassium buffering action of glial cells in the brain. Mutations in this gene have been associated with seizure susceptibility of common idiopathic generalized epilepsy syndromes.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Zebrafish
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KCNJ10 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Fine mapping of a seizure susceptibility locus on mouse Chromosome 1: nomination of Kcnj10 as a causative gene Ferraro TN , et al. (2004) No -
2 Highly Cited Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility Buono RJ , et al. (2004) No -
3 Recent Recommendation Altered electroretinograms in patients with KCNJ10 mutations and EAST syndrome Thompson DA , et al. (2011) No -
4 Recent Recommendation The disruption of central CO2 chemosensitivity in a mouse model of Rett syndrome Zhang X , et al. (2011) No -
5 Primary Autism with seizures and intellectual disability: possible causative role of gain-of-function of the inwardly-rectifying K+ channel Kir4.1 Sicca F , et al. (2011) Yes -
6 Recent Recommendation Down-regulation of Kir4.1 in the cerebral cortex of rats with liver failure and in cultured astrocytes treated with glutamine: Implications for astrocytic dysfunction in hepatic encephalopathy Obara-Michlewska M , et al. (2011) No -
7 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy Klassen T , et al. (2011) No -
8 Recent Recommendation Integrated systems analysis reveals a molecular network underlying autism spectrum disorders Li J , et al. (2015) Yes -
9 Support Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy Sicca F , et al. (2016) Yes -
10 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No ID, epilepsy/seizures
11 Positive Association Association study between inwardly rectifying potassium channels 2.1 and 4.1 and autism spectrum disorders Sun C , et al. (2018) Yes -
12 Support - Zhou X et al. (2022) Yes -
13 Support - Purvi Majethia et al. (2024) No DD
14 Support - Danijela Bataveljic et al. (2024) No -
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.994C>A p.Gln332Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.660C>T p.Thr220%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.52C>T p.Arg18Trp missense_variant Unknown - Unknown 25549968 Li J , et al. (2015)
c.53G>A p.Arg18Gln missense_variant Unknown - Simplex 27677466 Sicca F , et al. (2016)
c.53G>A p.Arg18Gln missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1092A>G p.Gln364= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.76C>T p.Arg26Ter stop_gained Familial Both parents - 38374498 Purvi Majethia et al. (2024)
c.53G>A p.Arg18Gln missense_variant Familial Maternal Simplex 27677466 Sicca F , et al. (2016)
c.53G>A p.Arg18Gln missense_variant Familial Paternal Simplex 27677466 Sicca F , et al. (2016)
c.250G>A p.Val84Met missense_variant Familial Maternal Simplex 21458570 Sicca F , et al. (2011)
c.53G>A p.Arg18Gln missense_variant Familial Maternal Multiplex 21458570 Sicca F , et al. (2011)
c.1043G>A p.Arg348His missense_variant Familial Paternal Simplex 27677466 Sicca F , et al. (2016)
c.170C>T p.Thr57Ile missense_variant Familial Both parents - 27848944 Trujillano D , et al. (2016)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1-10731C>A - intron_variant - - - 30304693 Sun C , et al. (2018)
c.811C>T p.Arg271Cys missense_variant - - - 15120748 Buono RJ , et al. (2004)
SFARI Gene score
2

Strong Candidate

Rare mutations in the KCNJ10 gene have been identified with autism (Sicca et al., 2011). In particular, that study found two non-synonymous SNPs (P18Q and V84M) in unrelated individuals with a seizure disorder who also have ASD and ID. Both of these mutations were shown to be functional in heterologous systems. Sicca et al., 2016 identified missense variants in KCNJ10 in additional ASD cases with or without co-morbid epilepsy/EEG abnormalities; functional analysis of these variants in astrocyte-like cells demonstrated gain-of-function effects. In addition, genetic association has been found between KCNJ10 and seizure susceptibility in patients with epilepsy (Buono et al., 2004).

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Rare mutations in the KCNJ10 gene have been identified with autism (Sicca et al., 2011). In particular, that study found two non-synonymous SNPs (P18Q and V84M) in unrelated individuals with a seizure disorder who also have ASD and ID. Both of these mutations were shown to be functional in heterologous systems. Sicca et al., 2016 identified missense variants in KCNJ10 in additional ASD cases with or without co-morbid epilepsy/EEG abnormalities; functional analysis of these variants in astrocyte-like cells demonstrated gain-of-function effects. In addition, genetic association has been found between KCNJ10 and seizure susceptibility in patients with epilepsy (Buono et al., 2004).

Reports Added
[New Scoring Scheme]
10/1/2018
3
icon
3

Decreased from 3 to 3

Description

Rare mutations in the KCNJ10 gene have been identified with autism (Sicca et al., 2011). In particular, that study found two non-synonymous SNPs (P18Q and V84M) in unrelated individuals with a seizure disorder who also have ASD and ID. Both of these mutations were shown to be functional in heterologous systems. Sicca et al., 2016 identified missense variants in KCNJ10 in additional ASD cases with or without co-morbid epilepsy/EEG abnormalities; functional analysis of these variants in astrocyte-like cells demonstrated gain-of-function effects. In addition, genetic association has been found between KCNJ10 and seizure susceptibility in patients with epilepsy (Buono et al., 2004).

Reports Added
[Association study between inwardly rectifying potassium channels 2.1 and 4.1 and autism spectrum disorders.2018]
10/1/2016
S
icon
3

Increased from S to 3

Description

Rare mutations in the KCNJ10 gene have been identified with autism (Sicca et al., 2011). In particular, that study found two non-synonymous SNPs (P18Q and V84M) in unrelated individuals with a seizure disorder who also have ASD and ID. Both of these mutations were shown to be functional in heterologous systems. Sicca et al., 2016 identified missense variants in KCNJ10 in additional ASD cases with or without co-morbid epilepsy/EEG abnormalities; functional analysis of these variants in astrocyte-like cells demonstrated gain-of-function effects. In addition, genetic association has been found between KCNJ10 and seizure susceptibility in patients with epilepsy (Buono et al., 2004).

Reports Added
[Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
1/1/2015
S
icon
S

Increased from S to S

Description

Rare mutations in the KCNJ10 gene have been identified with autism (Sicca et al., 2011). In particular, that study found two non-synonymous SNPs (P18Q and V84M) in unrelated individuals with a seizure disorder who also have ASD and ID. Both of these mutations were shown to be functional in heterologous systems. In addition, genetic association has been found between KCNJ10 and seizure susceptibility in patients with epilepsy (Buono et al., 2004).

Reports Added
[Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015]
Krishnan Probability Score

Score 0.58577567594141

Ranking 518/25841 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 0.59838882297069

Ranking 5005/18225 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 0.86293597501463

Ranking 3974/18665 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 -0.242678066937

Ranking 16248/20870 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
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
KCNJ16 potassium inwardly-rectifying channel, subfamily J, member 16 Human Protein Binding 3773 Q9NPI9
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