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.
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
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;
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;
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;
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;
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;
