Cation leak through the ATP1A3 pump causes spasticity and intellectual disability

April 12, 2023

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

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 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.

  1. Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  3. Texas Children’s Hospital, Houston, TX, 77030, USA.
  4. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
  5. Children’s National Rare Disease Institute, Children’s National Hospital, Washington, DC 20012, USA.
  6. Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  7. Zentrum Für Labormedizin, St. Gallen, 9001, Switzerland.
  8. Praxis Für Humangenetik Tübingen, Tuebingen, 72076, Germany.
  9. CeGaT GmbH, Tuebingen, 72076, Germany.
  10. Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, 21205, USA.
  11. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
  12. GeneDX, Gaithersburg, MD, 20879, USA.
  13. Section of Pediatric Neurology, Department of Pediatrics, Comer Children’s Hospital, University of Chicago, Chicago, IL, 60637, USA.
  14. Genomic Medicine Center, Children’s Mercy Research Institute, Kansas City, MO, USA.
  15. University of Missouri Kansas City School of Medicine, Kansas City, MO, USA.
  16. Department of Pathology and Laboratory Medicine, Children’s Mercy Hospital, Kansas City, MO, USA.
  17. Department of Genetics, Children’s Mercy Hospital, Kansas City, MO, USA.
  18. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
  19. Departments of Physical Medicine & Rehabilitation and Neurosurgery, Baylor College of Medicine, Houston, TX, 77030, USA.
  20. Department of Pediatric Neurology. La Paz University Hospital, Madrid, Spain.
  21. La Paz University Hospital Health Research Institute (FIBHULP), IdiPaz, Madrid, Spain.
  22. Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Spain.
  23. Department of Genetics, Genetic Service, La Paz University Hospital, Madrid, Spain.
  24. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
  25. Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
  26. Flow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA.
  27. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.