ArticleNeurobiology of disease2019
Factors in the disease severity of ATP1A3 mutations: Impairment, misfolding, and allele competition.
Article in Neurobiology of disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 43 citations in OpenAlex.
- ATP1A3-related neurological disorders: updated insights into clinical heterogeneity, molecular mechanisms and precision therapeutics.Neurogenetics · 2026Review
- Clinical and Genetic Spectrum ofNeurology. Genetics · 2026Article
- Mechanism of Rescue of NaInternational journal of molecular sciences · 2026Article
- Functional impact of the ATP1A3-p.A813V variant: insights into a calcium-driven hyperexcitability cascade in rapid-onset dystonia-Parkinsonism.Journal of translational medicine · 2026Article
- Caenorhabditis elegans models of alternating hemiplegia of childhood have dominant neuromuscular junction defects.Disease models & mechanisms · 2026Article
- Article
- Alternating Hemiplegia of Childhood andNeurology. Genetics · 2025Article
- Olfactory-Guided Behavior Uncovers Imaging and Molecular Signatures of Alzheimer's Disease Risk.Brain sciences · 2025Article
- Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice.Neurobiology of disease · 2025Article
- Smelling the Risk: Early Olfactory Deficits, Brain Networks, and Blood Markers of Alzheimer's Disease Risk in Humanized APOE Mice.bioRxiv : the preprint server for biology · 2025Article
- Phenotype Distinctions in Mice Deficient in the Neuron-Specific α3 Subunit of Na,K-ATPase:eNeuro · 2024Article
- Na,K-ATPase Expression Can Be Limited Post-Transcriptionally: A Test of the Role of the Beta Subunit, and a Review of Evidence.International journal of molecular sciences · 2024Review
- Article
- ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress.Disease models & mechanisms · 2024Article
- Article
- Cation leak through the ATP1A3 pump causes spasticity and intellectual disability.Brain : a journal of neurology · 2023Article
- Rapid-onset dystonia-parkinsonism is associated with reduced cerebral blood flow without gray matter changes.Frontiers in neurology · 2023Article
- Temperature instability of a mutation at a multidomain junction in Na,K-ATPase isoform ATP1A3 (p.Arg756His) produces a fever-induced neurological syndrome.The Journal of biological chemistry · 2023Article
- The role ofFrontiers in cellular neuroscience · 2023Review
- The Future of Genetic Disease Studies: Assembling an Updated Multidisciplinary Toolbox.Frontiers in cell and developmental biology · 2022Article
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Authors and funding
13 authors at 5 institutions in 2 countries.
Funding
Abstract
Dominant mutations of ATP1A3, a neuronal Na,K-ATPase α subunit isoform, cause neurological disorders with an exceptionally wide range of severity. Several new mutations and their phenotypes are reported here (p.Asp366His, p.Asp742Tyr, p.Asp743His, p.Leu924Pro, and a VUS, p.Arg463Cys). Mutations associated with mild or severe phenotypes [rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), or early infantile epileptic encephalopathy (EIEE)] were expressed in HEK-293 cells. Paradoxically, the severity of human symptoms did not correlate with whether there was enough residual activity to support cell survival. We hypothesized that distinct cellular consequences may result not only from pump inactivation but also from protein misfolding. Biosynthesis was investigated in four tetracycline-inducible isogenic cell lines representing different human phenotypes. Two cell biological complications were found. First, there was impaired trafficking of αβ complex to Golgi apparatus and plasma membrane, as well as changes in cell morphology, for two mutations that produced microcephaly or regions of brain atrophy in patients. Second, there was competition between exogenous mutant ATP1A3 (α3) and endogenous ATP1A1 (α1) so that their sum was constant. This predicts that in patients, the ratio of normal to mutant ATP1A3 proteins will vary when misfolding occurs. At the two extremes, the results suggest that a heterozygous mutation that only impairs Na,K-ATPase activity will produce relatively mild disease, while one that activates the unfolded protein response could produce severe disease and may result in death of neurons independently of ion pump inactivation.
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