Cation Leak Through the ATP1A3 Pump Causes Spasticity and Intellectual Disability

Authors

Daniel G Calame
Cristina Moreno Vadillo
Seth Berger
Timothy Lotze
Marwan Shinawi
Javaher Poupak
Corina Heller
Julie Cohen
Richard Person
Aida Telegrafi
Chalongchai Phitsanuwong
Kaylene Fiala
Isabelle Thiffault
Florencia Del Viso
Dihong Zhou
Emily A Fleming
Tomi Pastinen
Ali Fatemi
Sruthi Thomas
Samuel I Pascual
Rosa J Torres
Carmen Prior
Clara Gómez-González
Saskia Biskup
James R Lupski
Dragan Maric
Miguel Holmgren
Debra Regier
Sho T Yano

Publication Date

8-1-2023

Journal

Brain

DOI

10.1093/brain/awad124

PMID

37043503

PMCID

PMC10393399

PubMedCentral® Posted Date

4-12-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Mutation, Syndrome, Intellectual Disability, Cerebellar Ataxia, Phenotype, Muscle Spasticity, Cations, Sodium-Potassium-Exchanging ATPase, ATP1A3, sodium-potassium ATPase, neurodevelopmental disorders, spastic paraparesis, spasticity

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.