Cation leak through the ATP1A3 pump causes spasticity and intellectual disability.

TitleCation leak through the ATP1A3 pump causes spasticity and intellectual disability.
Publication TypeJournal Article
Year of Publication2023
AuthorsCalame, DG, Vadillo, CMoreno, Berger, S, Lotze, T, Shinawi, M, Poupak, J, Heller, C, Cohen, J, Person, R, Telegrafi, A, Phitsanuwong, C, Fiala, K, Thiffault, I, Del Viso, F, Zhou, D, Fleming, EA, Pastinen, T, Fatemi, A, Thomas, S, Pascual, SI, Torres, RJ, Prior, C, Gómez-González, C, Biskup, S, Lupski, JR, Maric, D, Holmgren, M, Regier, D, Yano, ST
Date Published2023 Aug 01
KeywordsCations, Cerebellar Ataxia, Humans, Intellectual Disability, Muscle Spasticity, Mutation, Phenotype, Sodium-Potassium-Exchanging ATPase, Syndrome

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.

Alternate JournalBrain
PubMed ID37043503
PubMed Central IDPMC10393399
Grant ListT32 GM007526 / GM / NIGMS NIH HHS / United States
P50 HD103538 / HD / NICHD NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
T32 NS043124 / NS / NINDS NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States

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