Cation leak through the ATP1A3 pump causes spasticity and intellectual disability

April 12, 2023

Daniel G Calame 1 2 3Cristina Moreno Vadillo 4Seth Berger 5Timothy Lotze 1 3Marwan Shinawi 6Javaher Poupak 7Corina Heller 8 9Julie Cohen 10 11Richard Person 12Aida Telegrafi 12Chalongchai Phitsanuwong 13Kaylene Fiala 13Isabelle Thiffault 14 15 16Florencia Del Viso 14 16Dihong Zhou 15 17Emily A Fleming 17Tomi Pastinen 14 15Ali Fatemi 10 11 18Sruthi Thomas 19Samuel I Pascual 20Rosa J Torres 21 22Carmen Prior 23Clara Gómez-González 23Saskia Biskup 8 9James R Lupski 2 3 24 25Dragan Maric 26Miguel Holmgren 4Debra Regier 5Sho T Yano 27


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 fulfill 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 favoring 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.

Keywords: ATP1A3; neurodevelopmental disorders; sodium-potassium ATPase; spastic paraparesis; spasticity.