HELP     Sign In
Search

Relevance to Autism

Two siblings from a British family with CAPOS syndrome and a p.Glu818Lys missense variant in ATP1A3 were diagnosed with autism spectrum disorder; this variant was also observed in two additional families with CAPOS syndrome in the absence of ASD (Demos et al., 2014). A probably damaging missense variant in ATP1A3 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Evaluation of the social behavior of the Myshkin mouse model of AHC2, which has an p.Ile810Asn mutation identical to one found in several AHC2 patients, including one patient with co-morbid autism (Yang et al., 2014; Panagiotakaki et al., 2015), identified deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test (Kirshenbaum et al., 2016). A second de novo missense variant that was predicted to be damaging was observed in an ASD proband from a Japanese trio in Takata et al., 2018. TADA analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified ATP1A3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

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. This gene encodes an alpha 3 catalytic subunit. Heterozygous variants in ATP1A3 are responsible for alternating hemiplegia of childhood 2 (AHC2; OMIM 614820) and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (OMIM 601338).

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
A novel recurrent mutation in ATP1A3 causes CAPOS syndrome.
CAPOS syndrome
ASD
Support
Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice.
DD, epilepsy/seizures
Support
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.
Epilepsy/seizures
DD/ID
Support
Exome Sequencing in 200 Intellectual Disability/Autistic Patients: New Candidates and Atypical Presentations
ID
Epilepsy/seizures
Support
ATP1A3 mutations and genotype-phenotype correlation of alternating hemiplegia of childhood in Chinese patients.
Alternating hemiplegia of childhood 2
Support
Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.
ID
Epileptic encephalopathy, stereotypies
Support
De novo variants in neurodevelopmental disorders-experiences from a tertiary care center
DD, epilepsy/seizures
Support
Clinical exome sequencing: results from 2819 samples reflecting 1000 families.
CAPOS syndrome
Support
Exome sequencing in paediatric patients with movement disorders
ID
Support
Mosaicism in ATP1A3-related disorders: not just a theoretical risk.
Ataxia, cerebellar atrophy
Epilepsy/seizures, autistic features
Support
Mutational and phenotypic expansion of ATP1A3-related disorders: Report of nine cases
Alternating hemiplegia of childhood 2
ID, epilepsy/seizures, rapid-onset dystonia-parkin
Support
A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia.
SCZ
Support
De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-well...
ASD
Support
Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients.
Alternating hemiplegia of childhood 2
Recent Recommendation
Deficits in social behavioral tests in a mouse model of alternating hemiplegia of childhood.
Recent Recommendation
De novo ATP1A3 variants cause polymicrogyria
DD, epilepsy/seizures
ID
Recent Recommendation
Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder.
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN829R001 
 missense_variant 
 c.2446G>A 
 p.Asp816Asn 
 Familial 
 Maternal 
 Multi-generational 
 GEN829R002 
 missense_variant 
 c.2452G>A 
 p.Asp818Asn 
 Familial 
 Paternal 
 Multi-generational 
 GEN829R003 
 missense_variant 
 c.2446G>A 
 p.Asp816Asn 
 Familial 
 Maternal 
 Multi-generational 
 GEN829R004 
 missense_variant 
 c.926T>C 
 p.Phe309Ser 
 De novo 
 NA 
  
 GEN829R005 
 missense_variant 
 c.385G>A 
 p.Val129Met 
 De novo 
 NA 
  
 GEN829R006 
 missense_variant 
 c.2116G>A 
 p.Glu706Lys 
 De novo 
 NA 
 Multiplex 
 GEN829R007 
 missense_variant 
 c.2266C>T 
 p.Arg756Cys 
 De novo 
 NA 
 Multiplex 
 GEN829R008 
 missense_variant 
 c.2452G>A 
 p.Asp818Asn 
 De novo 
 NA 
  
 GEN829R009 
 missense_variant 
 c.2224G>T 
 p.Asp742Tyr 
 De novo 
 NA 
  
 GEN829R010 
 missense_variant 
 c.499A>G 
 p.Met167Val 
 De novo 
 NA 
  
 GEN829R011 
 missense_variant 
 c.1765G>T 
 p.Val589Leu 
 De novo 
 NA 
 Simplex 
 GEN829R012 
 missense_variant 
 c.449C>T 
 p.Ser150Phe 
 De novo 
 NA 
  
 GEN829R013 
 missense_variant 
 c.2266C>T 
 p.Arg756Cys 
 De novo 
 NA 
 Simplex 
 GEN829R014 
 missense_variant 
 c.2041G>A 
 p.Ala681Thr 
 De novo 
 NA 
  
 GEN829R015 
 missense_variant 
 c.2552A>C 
 p.Gln851Pro 
 De novo 
 NA 
  
 GEN829R016 
 missense_variant 
 c.2479A>T 
 p.Arg827Trp 
 De novo 
 NA 
  
 GEN829R017 
 missense_variant 
 c.410C>A 
 p.Ser137Tyr 
 Unknown 
  
  
 GEN829R018 
 missense_variant 
 c.2429T>G 
 p.Ile810Ser 
 De novo 
 NA 
  
 GEN829R019 
 missense_variant 
 c.2401G>A 
 p.Asp801Asn 
 De novo 
 NA 
  
 GEN829R020 
 missense_variant 
 c.2600G>T 
 p.Gly867Val 
 Unknown 
  
  
 GEN829R021 
 missense_variant 
 c.2425G>C 
 p.Ala809Pro 
 De novo 
 NA 
  
 GEN829R022 
 missense_variant 
 c.2263G>T 
 p.Gly755Cys 
 Unknown 
  
  
 GEN829R023 
 missense_variant 
 c.2401G>A 
 p.Asp801Asn 
 Unknown 
  
  
 GEN829R024 
 missense_variant 
 c.2443G>A 
 p.Glu815Lys 
 De novo 
 NA 
 Simplex 
 GEN829R025 
 missense_variant 
 c.266G>C 
 p.Gly89Ala 
 De novo 
 NA 
 Simplex 
 GEN829R026 
 inframe_deletion 
 c.2976_2978del 
 p.Asp992del 
 De novo 
 NA 
 Simplex 
 GEN829R027 
 inframe_deletion 
 c.2976_2978del 
 p.Asp992del 
 De novo 
 NA 
 Simplex 
 GEN829R028 
 inframe_indel 
 c.2972_2982delinsTTGCGCATCTTCATCTG 
 p.Tyr991_Ile994delinsPheAlaHisLeuHisLeu 
 De novo 
 NA 
 Simplex 
 GEN829R029 
 inframe_insertion 
 c.3008_3009insACGAAATCC 
 p.Asp1003delinsGluArgAsnPro 
 De novo 
 NA 
 Simplex 
 GEN829R030 
 inframe_deletion 
 c.2570_2572del 
 p.Phe857del 
 De novo 
 NA 
 Simplex 
 GEN829R031 
 inframe_deletion 
 c.2560_2568del 
 p.Gly854_Phe856del 
 De novo 
 NA 
 Simplex 
 GEN829R032 
 missense_variant 
 c.1787G>A 
 p.Cys596Tyr 
 De novo 
 NA 
 Simplex 
 GEN829R033 
 missense_variant 
 c.2684A>C 
 p.Gln895Pro 
 De novo 
 NA 
 Simplex 
 GEN829R034 
 missense_variant 
 c.954C>G 
 p.Tyr318Ter 
 De novo 
 NA 
  
 GEN829R035 
 missense_variant 
 c.2116G>A 
 p.Glu706Lys 
 De novo 
 NA 
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
19
Deletion
 1
 
19
Duplication
 1
 
19
Deletion
 5
 

Model Summary

ATP1A3 mutant mice also called the Myshkin model has an I810N mutation and models deficits in social behaviors.

References

Type
Title
Author, Year
27276195
Deficits in social behavioral tests in a mouse model of alternating hemiplegia of childhood.

M_ATP1A3_1_HT_KI

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: ATP1A3 heterozygous null males were backcrossed for 20 generations to C57BL/6NCr strain; ATP1A3 mutant mice also called the Myshkin model has an I810N mutation identical to that found in an AHC patient with co-morbid autism;.
Allele Type: Targeted
Strain of Origin: Unreported
Genetic Background: C57BL/6NCr
ES Cell Line: Unreported
Mutant ES Cell Line: Unreported
Model Source: Charles River, Margate, UK

M_ATP1A3_1_HT_KI

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Nest building behavior1
Decreased
Description: Mutant mice nests were of consistently lower quality than those of wildtype controls; mutant mice had a lower propensity to shred the nesting material compared to wildtype mice; mutant mice nests had a lower height than wildtype mice; the difference between genotypes was not related to slower building;
Exp Paradigm: At 30min, 60min, 90min, 3h and 24h the percentage of nestlet that was shredded was recorded and the quality of the nest scored on a scale of 1 to 4; height of the nest was assessed at 24 h;
 Nest building assay
 8-14 weeks
Social memory1
Decreased
Description: In contrast to wt mice, mutant mice spent less time exploring the novel mouse and did not demonstrate a preference for explorig the novel mouse versus the previously introduced mouse; reduced social interaction was not due to deficient ambulation within the arena as there were no genotype specific differences in distance travelled during either phase of the test;
Exp Paradigm: 15 min habituation period; unfamiliar adult male aged 10 weeks was of c57bl/6 strain (stranger 1); time spent exploring stranger 1 or the empty cylinder in the first phase and time spent exploring either stranger 1 or 2 in the 2nd phase were recorded;
 Three-chamber social approach test
 8-14 weeks
Social approach1
Decreased
Description: In contrast to wt mice, mutant mice spent less time exploring the novel mouse and did not show a preference for exploring the novel mouse versus the empty container;
Exp Paradigm: 15 min habituation period; unfamiliar adult male aged 10 weeks was of c57bl/6 strain (stranger 1); time spent exploring stranger 1 or the empty cylinder in the first phase and time spent exploring either stranger 1 or 2 in the 2nd phase were recorded;
 Three-chamber social approach test
 8-14 weeks
Nest utilization behavior1
Decreased
Description: Mutant mice utilized the nest less than wildtype mice
Exp Paradigm: At 3h utilization of the nest was assessed by recording whether the mouse ws positioned inside or outside the nest;
 Nest utilization assay
 8-14 weeks
Maternal nurturing1
Decreased
Description: Mutant mice took longer than wt dams to initiate pup retrieval; this phenotype is unlikely to be caused by hearing loss; this phenotype is also unlikely to be caused by reduced usv emissions by mutant pups because pups were removed from communal nests containing on average 75% wt pups and 25% ht mutant pups;
Exp Paradigm: Compared pup retrieval latencies;
 Pup retrieval assay
 8-14 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
LRRN2 leucine rich repeat neuronal 2 10446 O75325 IP; LC-MS/MS
Huttlin EL , et al. 2015
RS1 retinoschisin 1 6247 O15537 Cell surface binding assay
Friedrich U , et al. 2011
S1PR1 Sphingosine 1-phosphate receptor 1 1901 P21453 IP; LC-MS/MS
Huttlin EL , et al. 2015
SPPL2B signal peptide peptidase like 2B 56928 Q8TCT7 IP; LC-MS/MS
Huttlin EL , et al. 2015
GRIN1 glutamate receptor, ionotropic, NMDA1 (zeta 1) 14810 P35438 IP; LC-MS/MS
Frank RA , et al. 2016
APP amyloid beta (A4) precursor protein 351 P05067 Surface plasmon resonance (SPR); IP/WB; Far Western Blot; Cell surface binding assay; IP; LC-MS/MS
Ohnishi T , et al. 2015
Grin1 glutamate receptor, ionotropic, N-methyl D-aspartate 1 24408 P35439 IP/WB
Akkuratov EE , et al. 2014
Grin2b glutamate receptor, ionotropic, N-methyl D-aspartate 2B 24410 Q00960 IP/WB
Akkuratov EE , et al. 2014
Slc6a5 solute carrier family 6 (neurotransmitter transporter, glycine), member 5 104245 Q761V0 IP/WB; Co-localization
de Juan-Sanz J , et al. 2013

HELP
Copyright © 2017 MindSpec, Inc.