ArticleBrain : a journal of neurology2023
Cation leak through the ATP1A3 pump causes spasticity and intellectual disability.
Article in Brain : a journal of neurology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 12 citations in OpenAlex.
- Clinical and Genetic Spectrum ofNeurology. Genetics · 2026Article
- Mechanism of Rescue of NaInternational journal of molecular sciences · 2026Article
- ATP1A3: Uncommon and wavering epilepsy phenotype in a rare variant.Epileptic disorders : international epilepsy journal with videotape · 2026Article
- Active conformations of neuronal NaNature communications · 2026Article
- The Movement Disorder Spectrum of ATP1A3-Related Disorders: Cross-Sectional Analysis and Video Archive of 88 Patients.Movement disorders : official journal of the Movement Disorder Society · 2026Observational
- CAPOS and Beyond:Molecular syndromology · 2025Article
- Surface Problem: Unveiling Extracellular Vesicles Surface Markers and Their Implications for Central Nervous System Diseases' Diagnosis and Treatment.Molecular neurobiology · 2025Review
- Association of the RecurrentNeurology. Genetics · 2025Article
- Opsoclonus in Alternating Hemiplegia of Childhood Secondary to ATP1A3 p.Gly803Arg.Movement disorders clinical practice · 2025Article
- GREGoR: Accelerating Genomics for Rare Diseases.ArXiv · 2024Article
- Novel mouse model of alternating hemiplegia of childhood exhibits prominent motor and seizure phenotypes.Neurobiology of disease · 2024Article
- ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress.Disease models & mechanisms · 2024Article
- Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
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Authors and funding
29 authors at 12 institutions in 4 countries.
Funding
Abstract
ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear. We report a novel recurrent variant, ATP1A3(NM_152296.5):c.2324C>T; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3-related disorder. Uniquely among known ATP1A3 variants, P775L causes leakage of sodium ions and protons into the cell, associated with impaired sodium binding/occlusion kinetics favouring states with fewer bound ions. These phenotypic and electrophysiologic studies demonstrate that ATP1A3:c.2324C>T; p.(Pro775Leu) results in mild ATP1A3-related phenotypes resembling complex hereditary spastic paraplegia or idiopathic spastic cerebral palsy. Cation leak provides a molecular explanation for this genotype-phenotype correlation, adding another mechanism to further explain phenotypic variability and highlighting the importance of biophysical properties beyond ion transport rate in ion transport diseases.
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