Alternative titles; symbols
HGNC Approved Gene Symbol: ATP1A3
SNOMEDCT: 702323008, 720634003;
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38) : 19:41,966,582-41,994,230 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | Alternating hemiplegia of childhood 2 | 614820 | Autosomal dominant | 3 |
| CAPOS syndrome | 601338 | Autosomal dominant | 3 | |
| Developmental and epileptic encephalopathy 99 | 619606 | Autosomal dominant | 3 | |
| Dystonia-12 | 128235 | Autosomal dominant | 3 |
The ATP1A3 gene encodes the alpha-3 catalytic subunit of the Na+/K(+)-ATPase transmembrane ion pump. The ATP1A3 isoform is exclusively expressed in neurons of various brain regions, including the basal ganglia, hippocampus, and cerebellum (summary by Rosewich et al., 2012).
Na+/K(+)-ATPases are heterooligomers of a catalytic alpha subunit, such as ATP1A3, and a glycosylated beta subunit. Na+/K(+)-ATPases catalyze ATP-driven exchange of 3 intracellular Na+ ions for 2 extracellular K+ ions across the plasma membrane. This exchange involves 2 major conformational changes, ATP hydrolysis and transitory phosphorylation of the ATPase, and temporary occlusion of 3 Na+ ions, followed by 2 K+ ions, within the ATPase in each conformation (summary by Rodacker et al., 2006).
Ovchinnikov et al. (1988) cloned ATP1A3, which they called alpha III, from a human brain cDNA library. The deduced 1,013-amino acid protein has a calculated molecular mass of 111.7 kD. Alpha III is predicted to have an N-terminal signal sequence, 7 transmembrane segments, and a cytoplasmic ATPase catalytic site.
By immunohistochemical analysis of rat and mouse retina, Wetzel et al. (1999) found that alpha-3 was expressed in photoreceptors, horizontal cells, bipolar cells, amacrine cells, and ganglion cells. In photoreceptors, alpha-3 was expressed in rod inner segments, as well as in cell somas in the outer nuclear layer and their presumptive terminals in the outer plexiform layer. Alpha-3 colocalized with beta-2 (ATP1B2; 182331) in photoreceptors and with beta-1 (ATP1B1; 182330) in horizontal cells. Various Na,K-ATPase isoforms exhibited marked changes in distribution during mouse postnatal development. Alpha-3 was detected in undifferentiated photoreceptor somas at birth, and was later targeted to inner segments and synaptic terminals.
Using in situ hybridization, Sugimoto et al. (2014) detected widespread Atp1a3 expression in mouse central nervous system, including expression in almost all brain regions and major neuronal cells.
Allocco et al. (2019) found expression of the Atp1a3 gene in neurons in all cortical layers of embryonic mouse brain. It was identified in differentiated neurons at the cortical plate and in neural stem cells at the ventricular zone lining the lateral ventricles; immunostaining was also observed in choroid plexus endothelial cells.
Ovchinnikov et al. (1988) determined that the ATP1A3 gene spans about 25 kb and that its protein-coding region includes 23 exons.
By Southern analysis of DNA from panels of rodent/human somatic cell hybrid lines, Yang-Feng et al. (1988) mapped the ATP1A3 gene to chromosome 19q12-q13.2. Harley et al. (1988) concluded that the order is qter--DM--APOC2--ATP1A3--cen.
Gross (2021) mapped the ATP1A3 gene to chromosome 19q13.2 based on an alignment of the ATP1A3 sequence (GenBank BC009282) with the genomic sequence (GRCh38).
Agrin (AGRN; 103320) mediates accumulation of acetylcholine receptors at the developing neuromuscular junction through its interaction with MUSK (601296), and it has also been implicated in brain development. Through biochemical studies, Hilgenberg et al. (2006) found that agrin bound Atp1a3 in mouse cortical neurons. Immunohistochemical analysis showed that Atp1a3 colocalized with agrin-binding sites at synapses. Agrin inhibited Atp1a3 activity, resulting in membrane depolarization and increased action potential frequency in mouse cortical neurons in culture and acute slice. An agrin fragment that acted as a competitive antagonist depressed action potential frequency, indicating that endogenous agrin regulates native Atp1a3 function. Hilgenberg et al. (2006) concluded that agrin regulates activity-dependent processes in neurons through its interaction with ATP1A3.
Dystonia 12
In 7 unrelated families with rapid-onset dystonia parkinsonism, or dystonia-12 (DYT12; 128235), de Carvalho Aguiar et al. (2004) identified 6 different heterozygous mutations in the ATP1A3 gene (182350.0001-182350.0006). Functional expression studies and structural analysis suggested that the mutations impaired enzyme activity or stability.
Anselm et al. (2009) and Blanco-Arias et al. (2009) reported de novo heterozygous ATP1A3 mutations (182350.0007 and 182350.0008, respectively) in patients with DYT12.
In Drosophila, Kaneko et al. (2014) identified a dominant missense mutation (A617T) in the calcium ATPase Serca gene (see SERCA2 (ATP2A2); 108740) that conferred temperature-sensitive motor uncoordination in a gain-of-function manner. The homologous residue is conserved by different type II P-type ATPases, including ATP1A2 (182340). Introduction of an R751Q mutation in the Drosophila Serca gene also caused a temperature-sensitive uncoordination phenotype. The corresponding residue in human SERCA2, ATP1A2, and ATP1A3 is mutated in the human diseases Darier disease (124200), FHM2 (602481), and dystonia-12, respectively. Cellular expression of Drosophila A617T resulted in temperature-induced decreased levels of stored calcium compared to wildtype, whereas cellular expression of R751Q elicited depletion of stored calcium even without heating. These calcium changes were due to leakage through the mutant channel pores that overwhelmed the pumping capacity of the cell. Similar results occurred after transfection of these mutations, as well as other disease-causing mutations that affected different parts of the protein, into mouse cells. Kaneko et al. (2014) concluded that ionic leakage is a gain-of-function mechanism that underlies a variety of dominant type II P-type ATPase-related diseases.
Alternating Hemiplegia of Childhood 2
In 82 of 105 patients with alternating hemiplegia of childhood-2 (AHC2; 614820), Heinzen et al. (2012) identified 19 different heterozygous mutations in the ATP1A3 gene (see, e.g., 182350.0009-182350.0012). The first mutations were identified through exome sequencing of affected individuals. Thirteen of the 18 mutations observed in sporadic cases were confirmed to occur de novo. Since it was possible that some variants represented polymorphisms, Heinzen et al. (2012) estimated that mutations in the ATP1A3 gene may be responsible for up to 74% of patients with sporadic, typical AHC. Several mutations were recurrent, and some occurred within hypermutable sequences. All patients had infantile onset of hemiplegia attacks, usually associated with episodes of quadriparesis, abnormal eye movements, autonomic signs, seizures, dystonia, ataxia, chorea, and developmental delay. Transfection of several of the mutations in HeLa cells showed protein levels similar to wildtype, but ATP1A3 activity was significantly decreased. In contrast, transfection of DYT12-associated mutations resulted in decreased protein levels as well as decreased activity. The report expanded the spectrum of phenotypes associated with mutations in the ATP1A3 gene.
Simultaneously and independent to the report of Heinzen et al. (2012), Rosewich et al. (2012) identified de novo heterozygous mutations in the ATP1A3 gene (see, e.g., 182350.0009; 182350.0010; 182350.0015-182350.0017) in 24 unrelated patients with AHC2. Mutations in the first 3 patients were found by whole-exome sequencing of 3 affected child-parent trios, and subsequent mutations were found by direct Sanger sequencing of the ATP1A3 gene in additional patients. There were 2 main recurrent mutations: D801N (182350.0009) and E815K (182350.0010), found in 9 (38%) and 7 (29%) patients, respectively, suggesting mutational hotspots. None of the mutations resulted in a truncated protein, although there was 1 splice site mutation (182350.0017). Functional studies of the variants and studies of patients cells were not performed. Rosewich et al. (2012) noted the phenotypic overlap between AHC2 and DYT12.
In 45 (95.7%) of 47 Chinese children with typical AHC2, Yang et al. (2014) identified 19 different heterozygous missense mutations in the ATP1A3 gene. Three mutation hotspots, D801N (182350.0009), E815K (182350.0010), and G947R (182350.0012 and 182350.0013), were detected in 14 (31.1%), 9 (20.0%), and 7 (15.6%) ATP1A3-positive patients, respectively. Except for 1 patient who had inherited a mutation from her affected mother, all patients for whom parental DNA was available were found to have de novo mutations. Heterozygous ATP1A3 mutations were also found in 4 additional Chinese patients with atypical AHC2 who had onset of the disorder after 18 months of age. The initial mutations were found by whole-exome sequencing of several patients, and the subsequent mutations were found by direct sequencing of the ATP1A3 gene in a larger cohort. Presence of the E815K mutation was associated with epilepsy. A review of published disease-associated ATP1A3 mutations suggested that mutations associated with AHC2 were predominantly located in the transmembrane domain, whereas those associated with DYT12 had no location bias. Molecular modeling of the variants identified 2 statistically significant molecular features, solvent accessibility and distance to metal ion, that distinguished disease-associated mutations from neutral variants. In vitro functional studies were not performed on any of the variants.
Cerebellar Ataxia, Areflexia, Pes Cavus, Optic Atrophy, and Sensorineural Hearing Loss
In 10 patients from 3 unrelated families with cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS; 601338), Demos et al. (2014) identified the same heterozygous missense mutation in the ATP1A3 gene (E818K; 182350.0014).
Developmental and Epileptic Encephalopathy 99
In 16 patients from 15 families with developmental and epileptic encephalopathy-99 (DEE99; 619606), Vetro et al. (2021) identified 14 heterozygous mutations in the ATP1A2 gene (see, e.g., 182350.0019-182350.0021). The mutations occurred de novo in all except for a mother and son pair (patients 14 and 15). Mutations were mostly missense, with a few small in-frame deletions or insertions. All occurred at conserved residues, and none were present in the gnomAD database. In vitro functional expression studies showed that all of the mutations caused variable functional defects in the Na+/(K+)ATPase. Variants with more severe functional deficits were associated with a more severe phenotype. The findings were consistent with a loss-of-function effect. Vetro et al. (2021) estimated that about 12% of ATP1A3 mutations may be associated with DEE. Polymicrogyria was estimated to occur in about 5.5% of patients with ATP1A3 mutations.
Associations Pending Confirmation
For discussion of a possible association between autosomal recessive congenital hydrocephalus due to aqueductal stenosis (see, e.g., 236635) and variation in the ATP1A3 gene, see 182350.0022 and 182350.0023.
Rosewich et al. (2014) identified 16 patients with AHC2 and 3 with DYT12 confirmed by genetic analysis. A review of the clinical and molecular findings of these patients and of 164 previously reported patients with ATP1A3 mutations indicated that although mutations were distributed over almost all protein domains, those affecting transmembrane and functional domains tended to be associated with AHC2 as the more severe phenotype. The majority of mutations associated with AHC2 were located in exons 17 and 18, whereas those associated with DYT12 were located in exons 8 and 14; however, there was overlap, particularly in exon 17. Clinical analysis suggested that the 2 disorders represent a continuous phenotypic spectrum, with intermediate phenotypes combining criteria of both conditions. Shared clinical characteristics of both disorders include asymmetric movement disorder, rostrocaudal gradient of involvement with prominent bulbar symptoms, and triggering of symptoms by different stressors.
Using a formulated questionnaire, Panagiotakaki et al. (2015) assessed clinical data from 155 patients with AHC, including 132 confirmed to have ATP1A3 mutations by genetic analysis. Among those with AHC2, the most frequent mutations were D801N (in 43%), E815K (in 16%), and G947R (182350.0012 and 182350.0013, which were considered together) (in 11%). E815K was associated with a severe phenotype, with greater intellectual and motor disability; D801N appeared to confer a milder phenotype; and G947R correlated with the most favorable prognosis. For those with epilepsy, the age at seizure onset was earlier for patients with the E815K or G947R mutations than for those with the D801N mutation. Several mutational clusters within the gene were identified.
Ashmore et al. (2009) identified 6 different EMS-induced missense mutations in the Atp1a2 and Atp1a3 genes in Drosophila. All mutations resulted in reduced respiration activity consistent with a loss of ATPase function and a hypomorphic effect. Different mutant strains exhibited some abnormalities, including progressive temperature-dependent paralysis, progressive stress-sensitive paralysis, and decreased locomotor activity in response to startle, suggesting a decrease in maximal locomotion capacity. Neuromuscular studies showed allele-specific pathology, including brain vacuoles and myopathology, and biochemical studies showed decreased metabolic rates. An unexpected finding was the some mutant strains had increased longevity, which was not related to caloric restriction. Low doses of ouabain showed a similar effect on longevity in control groups. Ashmore et al. (2009) suggested that these findings may be relevant for studying the pathogenesis of FHM2 and DYT12 (128235).
In a mouse mutagenesis screen, Clapcote et al. (2009) identified a mutant mouse strain, Myshkin (Myk), that showed autosomal dominant complex and partial and secondarily generalized seizures, a reduced threshold for seizures in hippocampal slices, and neuronal degeneration in the hippocampus. Heterozygous mice were also smaller than wildtype, and homozygosity for the mutation resulted in perinatal death. Positional cloning and functional analysis identified a heterozygous ile810-to-asn (I810N) substitution in the Atp1a3 gene as responsible for the phenotype. In vitro cellular functional expression studies showed that the I810N substitution disrupted enzymatic function. The mutant protein had 42% reduced activity in mouse brain, and the phenotype could be rescued by transfection of the wildtype gene, consistent with loss of function as a pathogenic mechanism. The findings indicated the importance of ion homeostasis in maintaining normal neuronal excitability.
Doganli et al. (2013) found that the 2 ATP1A3 orthologs in zebrafish, Atp1a3a and Atp1a3b, were expressed in distinct but overlapping sets of brain structures. Morpholino-mediated knockdown (KD) of either Atp1a3a or Atp1a3b caused dilation of brain ventricles. Dilation in Atp1a3a KD embryos was not rescued by coinjection of Atp1a3b, and Atp1a3b KD embryos were not rescued by coinjection of Atp1a3a. Atp1a3a KD also caused depolarization of the resting membrane potential of Rohon-Beard neurons, which are mechanosensory neurons localized in the dorsal spinal cord. Atp1a3a KD and Atp1a3b KD embryos showed abnormal but distinct spontaneous motility and responses to tactile stimuli. Proteomic analysis revealed that Atp1a3a KD and Atp1a3b KD altered expression of overlapping sets of genes.
Sugimoto et al. (2014) found that Atp1a3 +/- mice showed shortened stride length and decreased motor strength in hanging box test following restraint stress compared with wildtype mice. Male and female Atp1a3 +/- mice showed some differences in the effects of restraint stress.
Balestrini et al. (2020) studied electrocardiogram abnormalities in a mouse model with heterozygosity for an Atp1a3 D801N knock-in mutation (Mashl +/-). Compared to 15 wildtype mice, 3 Mashl +/- mice had an increased heart rate, prolonged QRS and PR interval, and a longer QTc interval. After intraamygdala injection of kainic acid to induce seizures, all mice had elevation of JT intervals. One of the Mashl +/- mice had a period with JT-segment depression, and 2 Mashl +/- mice died from atrioventricular block.
In a sporadic patient (Linazasoro et al., 2002) and affected members of a European family reported by Zaremba et al. (2004) with dystonia-12 (DYT12; 128235), de Carvalho Aguiar et al. (2004) identified a heterozygous 1838C-T transition in the ATP1A3 gene, resulting in a thr613-to-met (T613M) substitution at a highly conserved residue near the phosphorylation domain on the cytoplasmic face of the protein. The mutation was not identified in 500 northern European control chromosomes.
Brashear et al. (2007) identified the T613M mutation in a family with DYT12 reported by Pittock et al. (2000).
Rodacker et al. (2006) noted that T613 is universally conserved among Na+/K(+)-ATPases, H+/K(+)-ATPases, and Ca(2+)-ATPases. Using rat Atp1a1 (182310) for technical reasons, they presented evidence that the T613M substitution in ATP1A3 alters the affinity of ATP1A3 for Na+ and ATP and alters the conformation equilibrium in favor of the potassium-bound form.
In a patient with dystonia-12 (DYT12; 128235), de Carvalho Aguiar et al. (2004) identified a heterozygous 821T-C transition in the ATP1A3 gene, resulting in an ile274-to-thr (I274T) substitution in a highly conserved residue in the transmembrane domain of the protein. The mutation was not identified in 500 northern European control chromosomes. The patient had disease onset at age 37 years.
In a patient with dystonia-12 (DYT12; 128235), de Carvalho Aguiar et al. (2004) identified a heterozygous 829G-A transition in exon 8 of the ATP1A3 gene, resulting in a glu277-to-lys (E277K) substitution in a highly conserved residue in the transmembrane domain of the protein. The mutation was not identified in 500 northern European control chromosomes. The patient had disease onset at age 20 years.
Tarsy et al. (2010) identified the E277K mutation in a 29-year-old woman of African Caribbean descent with DYT12. She had onset at age 26 years of weakness and flexion of the left hand and ankle, which progressed rapidly over the next few years to become frank dystonia of the left arm and bulbar symptoms, including dysphagia, laryngeal dysfunction with task-specific dysphonia, and oropharyngeal dysmotility. She also had mild parkinsonism, with hypomimia and wide-based gait. Treatment with oral trihexyphenidyl and botulinum injection into selected laryngeal muscles resulted in clinical improvement.
In 12 affected members of a family with dystonia-12 (DYT12; 128235) reported by Dobyns et al. (1993), de Carvalho Aguiar et al. (2004) identified a heterozygous 2273T-G transversion in the ATP1A3 gene, resulting in an ile758-to-ser (I758S) substitution in a highly conserved residue in the transmembrane domain of the protein. The mutation was not identified in 500 northern European control chromosomes.
In 2 affected members of a family with dystonia-12 (DYT12; 128235), de Carvalho Aguiar et al. (2004) identified a heterozygous 2338T-C transition in the ATP1A3 gene, resulting in a phe780-to-leu (F780L) substitution in a highly conserved residue in the transmembrane region of the protein close to the extracellular surface. The mutation was not identified in 500 northern European control chromosomes.
Rodacker et al. (2006) noted that F780 is fully conserved in all known Na+/K(+)-ATPases from different species. Using rat Atp1a1 for technical reasons, they presented evidence that the F780L substitution reduced the affinity of ATP1A3 for Na+ and reduced the V(max) for ATP-dependent phosphorylation. The mutation was not expected to affect either the affinity of ATP1A3 for K+ nor the K(+)-induced dephosphorylation event.
In 4 affected members of a family with dystonia-12 (DYT12; 128235) reported by Brashear et al. (1997), de Carvalho Aguiar et al. (2004) identified a heterozygous 2401G-T transversion in the ATP1A3 gene, resulting in an asp801-to-tyr (D801Y) substitution in a highly conserved residue in the transmembrane region of the protein. The mutation was not identified in 500 northern European control chromosomes.
Dystonia 12
In a boy with early-onset dystonia-12 (DYT12; 128235) at age 4 years, Anselm et al. (2009) identified a heterozygous de novo 2767G-A transition in exon 20 of the ATP1A3 gene, resulting in an asp923-to-asn (D923N) substitution. The mutation was not found in 338 Caucasian control chromosomes. The substitution was predicted to occur in a residue buried in the membrane close to the ion-binding residue gln920, suggesting that it may affect enzyme activity. He was born of an unaffected Caucasian father and Chinese mother. The onset of dystonia was abrupt, occurring after mild trauma to the forehead. He developed mutism, eye convergence, and inability to walk, which later evolved into severe dystonia, severe dysarthria, and drooling. The condition stabilized over several months, and he showed mild improvement over the next 8 years. About a year after onset, he developed unusual episodes of flaccidity lasting for hours, later replaced by shorter episodes of stiffness. Treatment with L-DOPA was not effective. At the time of the report, he had bulbar symptoms, striking oromotor dystonia with inability to speak or swallow well, and apraxia.
Alternating Hemiplegia of Childhood 2
Yang et al. (2014) identified a de novo heterozygous D923N mutation in a Chinese boy with atypical alternating hemiplegia of childhood-2 (AHC2; 614820). The phenotype was considered atypical due to relatively late onset of symptoms at age 30 months. Otherwise, the boy had typical features of quadriplegia as well as abnormal eye movements, dystonia, and developmental delay.
In a 16-year-old female with dystonia-12 (DYT12; 128235), Blanco-Arias et al. (2009) reported a de novo heterozygous 3-bp duplication (3191dupTAC) in exon 23 of the ATP1A3 gene, resulting in duplication of tyr1013, the C-terminal amino acid of the protein before the stop codon. The mutation was not found in either parent, her brother, or in 218 control individuals. HeLa cells expressing the mutant protein showed decreased survival in response to ouabain challenge, but no defect was detected in protein expression or plasma membrane targeting. Functional analysis demonstrated a drastic 40- to 50-fold reduction in Na+ affinity in the mutant. Blanco-Arias et al. (2009) suggested a crucial role for the C terminus of the alpha-subunit in the function of the Na+/K(+)-ATPase and emphasized a key impact of Na+ affinity in the pathophysiology of DYT12.
In 36 of 95 unrelated patients with alternating hemiplegia of childhood-2 (AHC2; 614820), Heinzen et al. (2012) identified a heterozygous 2401G-A transition in the ATP1A3 gene, resulting in an asp801-to-asn (D801N) substitution in the sixth transmembrane domain. The mutation was demonstrated to occur de novo in cases where parental material was available. All patients had infantile onset of hemiplegia attacks, usually associated with episodes of quadriparesis, abnormal eye movements, autonomic signs, seizures, dystonia, ataxia, chorea, and developmental delay. Transfection of the mutation in HeLa cells showed protein levels similar to wildtype, but ATP1A3 activity was significantly decreased. Evaluation of the crystal structure of the protein predicted that the D801N substitution would prevent the binding of potassium ions to the pump.
Rosewich et al. (2012) identified a de novo heterozygous D801N mutation in 9 (38%) of 24 AHC2 patients. D801N occurs in the functionally conserved C-terminal cation-transporting ATPase domain and the P-type ATPase domain that is also a transmembrane domain. Functional studies of the variant and studies of patient cells were not performed.
Yang et al. (2014) identified a de novo heterozygous D801N mutation in 14 unrelated Chinese children with AHC2. All had typical features of the disorder, including abnormal eye movements and developmental delay, but none had seizures.
In 19 patients with alternating hemiplegia of childhood-2 (AHC2; 614820), Heinzen et al. (2012) identified a heterozygous 2443G-A transition in the ATP1A3 gene, resulting in a glu815-to-lys (E815K) substitution in the sixth transmembrane domain. The mutation was shown to occur de novo in all patients whose parents were available for study. Transfection of the mutation in HeLa cells showed protein levels similar to wildtype, but ATP1A3 activity was significantly decreased.
Rosewich et al. (2012) identified a de novo heterozygous E815K mutation in 7 (29%) of 24 AHC2 patients. E815K occurs in the functionally conserved C-terminal cation-transporting ATPase domain and the P-type ATPase domain that is also a transmembrane domain. Functional studies of the variant and studies of patient cells were not performed.
Yang et al. (2014) identified a de novo heterozygous E815K mutation in 9 unrelated Chinese children with AHC2. Seven of the patients had epilepsy.
In 4 unrelated patients with alternating hemiplegia of childhood-2 (AHC2; 614820), Heinzen et al. (2012) identified a de novo heterozygous 2431T-C transition in the ATP1A3 gene, resulting in a ser811-to-pro (S811P) substitution in the sixth transmembrane domain. Transfection of the mutation in HeLa cells showed protein levels similar to wildtype, but ATP1A3 activity was significantly decreased.
In 5 patients with alternating hemiplegia of childhood-2 (AHC2; 614820), Heinzen et al. (2012) identified a heterozygous 2839G-A transition in the ATP1A3 gene, resulting in a gly947-to-arg (G947R) substitution in the ninth transmembrane domain. The mutation was shown to occur de novo in all patients whose parents were available for study.
Yang et al. (2014) identified a de novo heterozygous G947R mutation in 5 unrelated Chinese children with AHC2. This same amino acid substitution can also result from a c.2839G-C transversion (182350.0013).
In 3 unrelated Chinese children with alternating hemiplegia of childhood-2 (AHC2; 614820), Yang et al. (2014) identified a heterozygous c.2839G-C transversion in exon 21 of the ATP1A3 gene, resulting in a gly947-to-arg (G947R) substitution at a highly conserved residue. The mutation occurred de novo in 2 of the patients and was inherited from an affected mother in the third patient. This same amino acid substitution can also result from a c.2839G-A transition (182350.0012). One of the patients had so-called atypical AHC2, with onset at 30 months of age. The mutation was not found in the 1000 Genomes Project or Exome Sequencing Project databases, or in 100 normal controls.
In 10 patients from 3 unrelated families with cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS; 601338), including the original family reported by Nicolaides et al. (1996), Demos et al. (2014) identified a heterozygous c.2452G-A transition in the ATP1A3 gene, resulting in a glu818-to-lys (E818K) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing of 2 of the families and confirmed by Sanger sequencing, was filtered against the dbSNP (builds 129 and 130) and 1000 Genomes Project databases and was not found in 1,834 controls. The mutation occurred de novo in the oldest affected generation of 1 family, but haplotype analysis could not rule out the possibility of a remote relationship between the other 2 families. All families were of Caucasian European descent. Functional studies of the E818K variant were not performed, but Demos et al. (2014) postulated a gain-of-function effect.
In a German boy with CAPOS, Rosewich et al. (2014) identified a de novo heterozygous E818K mutation in the ATP1A3 gene. Functional studies were not performed.
Tranebjaerg et al. (2018) reported that residue 818 of ATP1A3 is located at the cytoplasmic side of transmembrane helix-6, where it forms a salt bridge with the backbone carbonyl of arg930, a residue that stabilizes the C terminus. Tranebjaerg et al. (2018) expressed ATP1A3 with the E818K mutation in Xenopus laevis oocytes. Electrophysiologic analysis showed that the mutation disrupted the C terminus, caused opening of the C-terminal structure of ATP1A3, and affected sodium binding to and release from the binding site in the molecule. Molecular dynamic simulations confirmed that E818K opened the C-terminal pathway, allowing rapid entry of water molecules toward the ion-binding site.
In a 19-year-old man with alternating hemiplegia of childhood-2 (AHC2; 614820), Rosewich et al. (2012) identified a de novo heterozygous c.2767G-T transversion (c.2767G-T, NM_152296.4) in exon 20 of the ATP1A3 gene, resulting in an asp923-to-tyr (D923Y) substitution at a highly conserved residue in the C-terminal cation ATPase domain. Functional studies of the mutation and studies of patient cells were not performed. The authors noted that a different substitution at this same residue (D923N; 182350.0007) has been identified in patients with dystonia-12 (DYT12; 128235).
In a 17-year-old girl with alternating hemiplegia of childhood-2 (AHC2; 614820), Rosewich et al. (2012) identified a de novo heterozygous c.821T-A transversion (c.821T-A, NM_152296.4) in exon 8 of the ATP1A3 gene, resulting in an ile274-to-asn (I274N) substitution at a highly conserved residue in the E1-E2 ATPase domain. Functional studies of the mutation and studies of patient cells were not performed. The authors noted that a different substitution at this same residue (I274T; 182350.0002) has been identified in patients with dystonia-12 (DYT12; 128235).
In a 24-year-old woman with alternating hemiplegia of childhood-2 (AHC2; 614820), Rosewich et al. (2012) identified a de novo heterozygous G-to-A transition in intron 18 of the ATP1A3 gene (c.2542+1G-A, NM_152296.4), predicted to result in exon skipping. Functional studies of the mutation and studies of patient cells were not performed.
In a 26-year-old man with dystonia-12 (DYT12; 128235), Sweadner et al. (2016) identified a de novo heterozygous c.946G-A transition (c.946G-A, NM_152296.3) in the ATP1A3 gene, resulting in a gly316-to-ser (G316S) substitution in the highly conserved fourth transmembrane domain and close to an ion binding pocket. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional studies showed that the mutation resulted in a growth defect when expressed in HEK293 cells, consistent with impaired Na/K-ATPase function. The patient had a somewhat unusual phenotype, presenting at age 19 with rapidly progressive ataxia and dysarthria and tremor, resulting in loss of independent ambulation, and minimal dystonia. Exome sequencing showed that the patient also carried a de novo heterozygous missense E482K variant in the UBQLN4 gene (605440), which may have played a role in the prominent cerebellar ataxia and cerebellar atrophy observed in this patient; functional studies of the UBQLN4 variant were not performed.
In a 2-month-old infant (patient 7) with lethal developmental and epileptic encephalopathy-99 (DEE99; 619606), Vetro et al. (2021) identified a de novo heterozygous c.875T-G transversion (c.875T-G, NM_152296.4) in the ATP1A3 gene, resulting in a leu292-to-arg (L292R) substitution at a conserved residue. The mutation was not present in the gnomAD database. In vitro studies showed that the mutation was unable to support growth and survival of COS1 cells in culture and interfered with Na+ and K+ affinity, resulting in nearly absent Na+/(K+)ATPase activity, consistent with a loss-of-function effect. The patient presented at birth with migrating focal seizures that evolved to almost continuous seizure activity with status epilepticus, resulting in death at 2 months of age.
In a 6-year-old girl (patient 8) with developmental and epileptic encephalopathy-99 (DEE99; 619606), Vetro et al. (2021) identified a de novo heterozygous c.947G-T transversion (c.947G-T, NM_152296.4) in the ATP1A3 gene, resulting in a gly316-to-val (G316V) substitution at a conserved residue. The mutation was not present in the gnomAD database. In vitro studies showed that the mutation was unable to support growth and survival of COS1 cells in culture and interfered with Na+ and K+ affinity, resulting in nearly absent Na+/(K+)ATPase activity, consistent with a loss-of-function effect. The patient had onset of migrating focal and severe generalized seizures at 4 years of age.
In a 7-year-old girl (patient 9) with developmental and epileptic encephalopathy-99 (DEE99; 619606), Vetro et al. (2021) identified a de novo heterozygous c.1081T-C transition (c.1081T-C, NM_152296.4) in the ATP1A3 gene, resulting in a ser361-to-pro (S361P) substitution at a conserved residue. The mutation was not present in the gnomAD database. In vitro studies showed that the mutation was unable to support growth and survival of COS1 cells in culture with decreased phosphorylation activity and nearly absent Na+/(K+)ATPase activity, consistent with a loss-of-function effect. The patient had onset of focal temporal seizures at 5 months of age.
This variant is classified as a variant of unknown significance because its contribution to congenital hydrocephalus due to aqueductal stenosis (see, e.g., 236635) has not been confirmed.
In a 23-year-old Caucasian woman with congenital hydrocephalus due to aqueductal stenosis, Allocco et al. (2019) identified compound heterozygous missense variants in the ATP1A3 gene: a c.55G-A transition (c.55G-A, NM_152296) in exon 2, resulting in an arg19-to-cys (R19C) substitution inherited from the unaffected mother, and a c.1387G-A transition in exon 11, resulting in an arg463-to-cys (R463C; 182350.0023) substitution inherited from the unaffected father. The variants were identified by whole-exome sequencing and confirmed by Sanger sequencing. The R19C variant was present in the heterozygous state at a low frequency in gnomAD (6.4 x 10(-5)). Both variants occurred at conserved residues and were predicted to have disruptive effects on protein stability, although functional studies of the variants and studies of patient cells were not performed. The patient had multiple brain malformations, including open schizencephaly, type 1 Chiari malformation, and dysgenesis of the corpus callosum. Clinical details were limited, but she was noted to have learning disabilities. The authors postulated that dysregulation of neural development may be the pathogenesis of the disorder in this patient.
This variant is classified as a variant of unknown significance because its contribution to congenital hydrocephalus due to aqueductal stenosis (see, e.g., 236635) has not been confirmed.
For discussion of the c.1387G-A transition (c.1387G-A, NM_152296) in exon 11 of the ATP1A3 gene, resulting in an arg463-to-cys (R463C) substitution, that was found in compound heterozygous state in a patient with congenital hydrocephalus due to aqueductal stenosis, by Allocco et al. (2019) see 182350.0022.
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