Document Type

Article

Publication Date

8-1-2023

Identifier

DOI: 10.1093/brain/awad124; PMCID: PMC10393399

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.

Journal Title

Brain : a journal of neurology

Volume

146

Issue

8

First Page

3162

Last Page

3171

MeSH Keywords

Humans; Mutation; Syndrome; Intellectual Disability; Cerebellar Ataxia; Phenotype; Muscle Spasticity; Cations; Sodium-Potassium-Exchanging ATPase

Keywords

ATP1A3; neurodevelopmental disorders; sodium-potassium ATPase; spastic paraparesis; spasticity

Comments

Grant support

This work is written by (a) US Government employee(s) and is in the public domain in the US.

Publisher's Link: https://doi.org/10.1093/brain/awad124

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