UNASSIGNED: We previously reported that ATP1A3 c.823G>C (p.Ala275Pro) mutant causes varying phenotypes of alternative hemiplegia of childhood and rapid-onset dystonia-parkinsonism in the same family. This study aims to investigate the function of ATP1A3 c.823G>C (p.Ala275Pro) mutant at the cellular and zebrafish models.
UNASSIGNED: ATP1A3 wild-type and mutant Hela cell lines were constructed, and ATP1A3 mRNA expression, ATP1A3 protein expression and localization, and Na+-K+-ATPase activity in each group of cells were detected. Additionally, we also constructed zebrafish models with ATP1A3 wild-type overexpression (WT) and p.Ala275Pro mutant overexpression (MUT). Subsequently, we detected the mRNA expression of dopamine signaling pathway-associated genes, Parkinson\'s disease-associated genes, and apoptosisassociated genes in each group of zebrafish, and observed the growth, development, and movement behavior of zebrafish.
UNASSIGNED: Cells carrying the p.Ala275Pro mutation exhibited lower levels of ATP1A3 mRNA, reduced ATP1A3 protein expression, and decreased Na+-K+-ATPase activity compared to wild-type cells. Immunofluorescence analysis revealed that ATP1A3 was primarily localized in the cytoplasm, but there was no significant difference in ATP1A3 protein localization before and after the mutation. In the zebrafish model, both WT and MUT groups showed lower brain and body length, dopamine neuron fluorescence intensity, escape ability, swimming distance, and average swimming speed compared to the control group. Moreover, overexpression of both wild-type and mutant ATP1A3 led to abnormal mRNA expression of genes associated with the dopamine signaling pathway and Parkinson\'s disease in zebrafish, and significantly upregulated transcription levels of bad and caspase-3 in the apoptosis signaling pathway, while reducing the transcriptional level of bcl-2 and the bcl-2/bax ratio.
UNASSIGNED: This study reveals that the p.Ala275Pro mutant decreases ATP1A3 protein expression and Na+/K+-ATPase activity. Abnormal expression of either wild-type or mutant ATP1A3 genes impairs growth, development, and movement behavior in zebrafish.

The ATP1A3 gene is associated with the development and progression of neurological diseases. However, the pathological function and therapeutic value of ATP1A3 in glioblastoma (GBM) remains unknown. In this study, we tried to explore the correlation between the ATP1A3 gene expression and immune features in GBM samples. We found that ATP1A3 gene expression levels showed significant negative correlation with immune checkpoints such as PD-L1, CTLA-4 and IDO1. Next, ATP1A3 gene expression levels showed significant negative correlation with the anti-cancer immune cell process, the immune score and stromal score. By grouping ATP1A3 expression levels, we found that that immunomodulator-related genes and tumor-associated immune cell effector gene expression levels were associated with lower ATP1A3 expression. In addition, immunotherapy prediction pathway activity and a majority of the anti-cancer immune cell process activity levels were also showed to be correlated with lower ATP1A3 gene expression. Further, nine prognostic factors were identified by prognostic analysis, and a GBM prognostic model (risk score) was established. We applied the model to the TCGA GBM training set sample and the GSE4412 validation set sample and found that patients in the high risk score subgroup had significantly shorter survival time, demonstrating the prognostic value and prognostic efficacy of the risk score. Furthermore, ATP1A3 overexpression has also been found to sensitize cancer cells to anti-PD-1 therapy. In conclusion, we showed that ATP1A3 is a highly promising treatment target in GBM and the risk score is an independent prognostic factor for cancer and can be used to help guide the prediction of survival time in patients with GBM.

The ATP1A3 gene, which encodes the Na+/K+-ATPase α3 catalytic subunit, plays a crucial role in both physiological and pathological conditions in the brain, and mutations in this gene have been associated with a wide variety of neurological diseases by impacting the whole infant development stages. Cumulative clinical evidence suggests that some severe epileptic syndromes have been linked to mutations in ATP1A3, among which inactivating mutation of ATP1A3 has been intriguingly found to be a candidate pathogenesis for complex partial and generalized seizures, proposing ATP1A3 regulators as putative targets for the rational design of antiepileptic therapies. In this review, we introduced the physiological function of ATP1A3 and summarized the findings about ATP1A3 in epileptic conditions from both clinical and laboratory aspects at first. Then, some possible mechanisms of how ATP1A3 mutations result in epilepsy are provided. We think this review timely introduces the potential contribution of ATP1A3 mutations in both the genesis and progression of epilepsy. Taken that both the detailed mechanisms and therapeutic significance of ATP1A3 for epilepsy are not yet fully illustrated, we think that both in-depth mechanisms investigations and systematic intervention experiments targeting ATP1A3 are needed, and by doing so, perhaps a new light can be shed on treating ATP1A3-associated epilepsy.

OBJECTIVE: In the past few decades, the prognosis of glioma patients has not significantly improved. Therefore, to provide more precise medical services for glioma patients, it is urgent to identify more clinically meaningful subtypes, establish more robust clinical prediction models, and find more effective therapeutic targets.
METHODS: Four distinct metabolic-associated subtypes were identified by the NMF algorithm based on metabolic genes (MEGs). A robust scoring system was constructed based on the differentially expressed genes (DEGs) screened from the four metabolic-associated subtypes with the LASSO regression algorithm and multivariate Cox regression analysis. Further analysis of scoring systems was done by different R packages. In addition, the ATP1A3 gene was screened and bioinformatics analysis of it was conducted on several public websites. GSEA software was utilized to search hallmark signaling pathways closely related to ATP1A3. Cytological experiments were used to investigate the role of ATP1A3 in the malignant progression of glioblastoma (GBM) cells.
RESULTS: Four metabolic-associated subtypes with significantly different clinicopathological characteristics were identified, and a robust scoring system with outstanding clinical application value was established. In addition, a tumor suppressor gene ATP1A3 was found, which is expected to be a potential therapeutic target for glioma.
CONCLUSIONS: This study is of great significance in the diagnosis, prognosis, and prediction of the response to immune checkpoint blockers (ICBs) for glioma patients. More importantly, this study found a potential therapeutic target for glioma.

The aim of this research is to study the phenotype, genotype, treatment strategies, and short-term prognosis of Chinese children with ATP1A3 (Na+/K+-ATPase alpha 3 gene)-related disorders in Southwest China. Patients with pathogenic ATP1A3 variants identified using next-generation sequencing were registered at the Children\'s Hospital of Chongqing Medical University from December 2015 to May 2019. We followed them as a cohort and analyzed their clinical data. Eleven patients were identified with de novo pathogenic ATP1A3 heterozygous variants. One (c.2542 + 1G > T, splicing) has not been reported. Eight patients with alternating hemiplegia of childhood (AHC), one with cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), and two with relapsing encephalopathy with cerebellar ataxia (RECA) were included. The initial manifestations of AHC included hemiplegia, oculomotor abnormalities, and seizures, and the most common trigger was an upper respiratory tract infection without fever. All patients had paroxysmal hemiplegic attacks during their disease course. The brain MRI showed no abnormalities. Six out of eight AHC cases reached a stable disease state after treatment. The initial symptom of the patient with CAPOS was ataxia followed by developmental regression, seizures, deafness, visual impairment, and dysarthria, and the brain MRI indicated mild cerebellar atrophy. No fluctuation was noted after using Acetazolamide. The initial manifestations of the two RECA cases were dystonia and encephalopathy, respectively. One manifested a rapid-onset course of dystonia triggered by a fever followed by dysarthria and action tremors, and independent walking was impossible. The brain MRI image was normal. The other one presented with disturbance of consciousness, seizures, sleep disturbance, tremor, and dyskinesias. The EEG revealed a slow background (δ activity), and the brain MRI result was normal. No response to Flunarizine was noted for them, and it took 61 and 60 months for them to reach a stable disease state, respectively.
CONCLUSIONS: Pathogenic ATP1A3 variants play an essential role in the pathogenesis of Sodium-Potassium pump disorders, and AHC is the most common phenotype. The treatment strategies and prognosis depend on the phenotype categories caused by different variation sites and types. The correlation between the genotype and phenotype requires further exploration.
BACKGROUND: • Pathogenic heterozygous ATP1A3 variants cause a spectrum of neurological phenotypes, and ATP1A3-disorders are viewed as a phenotypic continuum presenting with atypical and overlapping features. • The genotype-phenotype correlation of ATP1A3-disorders remains unclear.
BACKGROUND: • In this study, the genotypes and phenotypes of ATP1A3-related disorders from Southwest of China were described. The splice-site variation c.2542+1G>T was detected for the first time in ATP1A3-related disorders. • The prognosis of twins with AHC p. Gly947Arg was more serious than AHC cases with other variants, which was inconsistent with previous reports. The phenomenon indicated the diversity of the correlation between the genotype and phenotype.

UNASSIGNED: Rapid-onset dystonia parkinsonism (RDP) is a rare disease caused by ATP1A3 mutation with considerable clinical heterogeneity. Increased knowledge of RDP could be beneficial in its early diagnosis and treatment.
UNASSIGNED: This study aimed to summarize the gene mutation spectrum of ATP1A3 associated with RDP, and to explore the correlation of ATP1A3 variants with RDP clinical phenotypes.
UNASSIGNED: In this study, we reported two RDP patients from a family with a novel inherited ATP1A3 variant. Then, we reviewed and analyzed the available literature in English focused on ATP1A3-causative RDP. A total of 35 articles covering 15 families (59 patients) and 36 sporadic RDP cases were included in our analysis.
UNASSIGNED: The variant A813V (2438C>T) in ATP1A3 found in our cases was a novel mutant. Delays in diagnosis were common, with a mean delay time of 14 years. ATP1A3 had distinct RDP-related mutation hotspots, which consisted of exon8, 14, 17, and 18, and the most frequently occurring variants were T613M and I578S. Approximately 74.5% of patients have specific triggers before disease onset, and 82.1% of RDPs have stable symptoms within 1 month. The incidence rates of dystonia and bradykinesia are 100 and 88.1%, respectively. The onset site varied and exhibited a rostrocaudal gradient distribution pattern in 45% of patients with RDP. Approximately 63.6% of patients had mild improvement after receiving comprehensive interventions, especially in gait disturbance amelioration.
UNASSIGNED: In patients with acute and unexplained dystonia or bradykinesia, gene screening on ATP1A3 should be timely performed. When a diagnosis has been made, treatments that may be effective are to be attempted. Our study would be helpful for the early diagnosis and treatment of ATP1T3-related RDP.

UNASSIGNED: With detailed studies of ATP1A3-related diseases, the phenotypic spectrum of ATP1A3 has greatly expanded. This study aimed to potentially identify the mechanisms by which ATP1A3 caused neurological dysfunction by analyzing the clinical features and phenotypes of ATP1A3-related diseases, and exploring the distribution patterns of mutations in the subregions of the ATP1A3 protein, thus providing new and effective therapeutic approaches.
UNASSIGNED: Databases of PubMed, Online Mendelian Inheritance in Man, and Human Gene Mutation Database, Wanfang Data, and Embase were searched for case reports of ATP1A3-related diseases. Following case screening, we collected clinical information and genetic testing results of patients, and analyzed the disease characteristics on the clinical phenotype spectrum associated with mutations, genetic characteristics of mutations, and effects of drug therapy.
UNASSIGNED: We collected 902 clinical cases related to ATP1A3 gene. From the results of previous studies, we further clarified the clinical characteristics of ATP1A3-related diseases, such as alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism; cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss syndrome, and relapsing encephalopathy with cerebellar ataxia, frequency of mutations in different phenotypes and their distribution in gene and protein structures, and differences in mutations in different clinical phenotypes. Regarding the efficacy of drug treatment, 80 of the 124 patients with AHC were treated with flunarizine, with an effectiveness rate of ~64.5%.
UNASSIGNED: Nervous system dysfunction due to mutations of ATP1A3 gene was characterized by a group of genotypic-phenotypic interrelated disease pedigrees with multiple clinical manifestations. The presented results might help guide the diagnosis and treatment of ATP1A3-related diseases and provided new ideas for further exploring the mechanisms of nervous system diseases due to ATP1A3 mutations.

UNASSIGNED: The phenotypes of ATP1A3 gene mutations are diverse. Relapsing encephalopathy with cerebellar ataxia and fever-induced paroxysmal weakness and encephalopathy (FIPWE) are considered non-classical phenotypes caused by p.Arg756 mutations of ATP1A3.
UNASSIGNED: To summarize the clinical manifestations, treatment, and follow-up of Chinese patients with p.Arg756 mutations of ATP1A3.
UNASSIGNED: We analyzed the clinical features, treatment, and genotypes of eight children with p.Arg756 mutations of ATP1A3 who were treated in Beijing Children\'s Hospital from January 2014 to December 2019.
UNASSIGNED: Eight patients (six boys and two girls) were included; seven had been misdiagnosed with encephalitis. The age of onset ranged from 0.8 to 4.5 years. All patients had encephalopathy and had at least one episode of FIPWE. Cerebellar ataxia was present in nine episodes. Reversible splenial lesions of the corpus callosum were found in two patients in the acute phase. Three types of heterozygous ATP1A3 mutations were found: c.2267G > T (p.R756L) (patient 3 [P3]), c.2266C > T (p.R756C) (P2 and P4), and c.2267G > A (p.R756H) (P1, P5, P6, P7, and P8). Six mutations were de novo; two mutations were inherited. Both patients with p.R756C and one patient (P7) with p.R756H had four episodes of severe ataxia as the main manifestations. However, in the other three episodes, limb weakness was more prominent than ataxia. P5 with p.R756H exhibited overlap with FIPWE and rapid-onset dystonia-parkinsonism.
UNASSIGNED: Acute encephalopathy followed by febrile disease was characteristic of the disease in patients with p.Arg756 mutations of ATP1A3. However, the weakness and ataxia were variable. Phenotypic crossover and overlap were observed among these patients.

BACKGROUND: The spectrum of neurological diseases related to ATP1A3 gene mutations is highly heterogeneous and exhibits different phenotypes. Phenotype overlaps, including alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy, and rapid-onset dystonia-parkinsonism (RDP), can also occur at extremely low incidences. Currently, over 90 types of pathogenic mutations have been identified in ATP1A3.
METHODS: The family of a 2-year-11-month-old proband with AHC was recruited for this clinical investigation. The proband was screened for candidate mutation gene sites using next-generation sequencing and target-region capture technology. Sanger sequencing was used to identify carriers among family members.
RESULTS: The mother of the proband with AHC was diagnosed with dystonia (later diagnosed as RDP). The biochemical and immune indices of the proband and the mother were not abnormal. Moreover, brain imaging of the proband revealed no significant abnormalities. However, the electroencephalogram of the mother was mildly abnormal, with no spike wave discharge. Brain MRI revealed slight cerebellar atrophy. Electromyography revealed neurogenic damage, with a decrease in the conduction velocity of the left ulnar and radial nerves. Based on the sequencing data, both the proband and her mother carried c.823G > C p. (Ala275Pro) heterozygotes; other family members were not identified as carriers. With a PolyPhen-2 score of 0.997 and SIFT score of 0.001, this mutation can be considered damaging.
CONCLUSIONS: Family genotype-phenotype correlation analysis revealed that the phenotype and gene mutation were co-segregated, suggesting that it may be a pathogenic mutation.

Objective: The objective of this study is to analyze the genotype-phenotype correlation of patients with auditory neuropathy (AN), which is a clinical condition featuring normal cochlear responses and abnormal neural responses, and ATP1A3 c.2452 G > A (p.E818K), which has been generally recognized as a genetic cause of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. Methods: Four patients diagnosed as AN by clinical evaluation and otoacoustic emission and auditory brainstem responses were recruited and analyzed by next-generation sequencing to identify candidate disease-causing variants. Sanger sequencing was performed on the patients and their parents to verify the results, and short tandem repeat-based testing was conducted to confirm the biological relationship between the parents and the patients. Furthermore, cochlear implantation (CI) was performed in one AN patient to reconstruct hearing. Results: Four subjects with AN were identified to share a de novo variant, p.E818K in the ATP1A3 gene. Except for the AN phenotype, patients 1 and 2 exhibited varying degrees of neurological symptoms, implying that they can be diagnosed as CAPOS syndrome. During the 15 years follow-up of patient 1, we observed delayed neurological events and progressive bilateral sensorineural hearing loss in pure tone threshold (pure tone audiometry, PTA). Patient 2 underwent CI on his left ear, and the result was poor. The other two patients (patient 3 and patient 4, who were 8 and 6 years old, respectively) denied any neurological symptoms. Conclusion: ATP1A3 p.E818K has rarely been documented in the Chinese AN population. Our study confirms that p.E818K in the ATP1A3 gene is a multiethnic cause of AN in Chinese individuals. Our study further demonstrates the significance of genetic testing for this specific mutation for identifying the special subtype of AN with somewhat favorable CI outcome and offers a more accurate genetic counseling about the specific de novo mutation.