Comparative analysis of alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism ATP1A3 mutations reveals functional deficits, which do not correlate with disease severity

Elinor Lazarov,Merle Hillebrand,Simone Schröder,Katharina Ternka,Julia Hofhuis,Andreas Ohlenbusch,Alonso Barrantes-Freer,Luis A Pardo,Marlene U Fruergaard,Poul Nissen,Knut Brockmann,Jutta Gärtner,Hendrik Rosewich

doi:10.1016/j.nbd.2020.105012

Abstract

Heterozygous mutations in the ATP1A3 gene, coding for an alpha subunit isoform (α3) of Na+/K+-ATPase, are the primary genetic cause for rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). Recently, cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS), early infantile epileptic encephalopathy (EIEE), childhood rapid onset ataxia (CROA) and relapsing encephalopathy with rapid onset ataxia (RECA) extend the clinical spectrum of ATP1A3 related disorders. AHC and RDP demonstrate distinct clinical features, with AHC symptoms being generally more severe compared to RDP. Currently, it is largely unknown what determines the disease severity, and whether severity is linked to the degree of functional impairment of the α3 subunit.Here we compared the effect of twelve different RDP and AHC specific mutations on the expression and function of the α3 Na+/K+-ATPase in transfected HEK cells and oocytes. All studied mutations led to functional impairment of the pump, as reflected by lower survival rate and reduced pump current. No difference in the extent of impairment, nor in the expression level, was found between the two phenotypes, suggesting that these measures of pump dysfunction do not exclusively determine the disease severity.

Highlights

The P-type Na+/K+-ATPases are integral membrane proteins that actively transport three sodium ions (Na+) out of the cell and two potassium ions (K+) into the cell, using the energy of ATP hydrolysis
Mutations in ATP1A3 have been linked to various neurological disorders, including rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood
RDP is a rare dystonic movement disorder characterized by a slow or an abrupt onset of dystonia with features of parkinsonism that can last from a few minutes to one month in combination with prominent bulbar findings

Summary

Introduction

The P-type Na+/K+-ATPases are integral membrane proteins that actively transport three sodium ions (Na+) out of the cell and two potassium ions (K+) into the cell, using the energy of ATP hydrolysis. Thereby, they establish and maintain an electrochemical gradient at the plasma membrane, which is essential for diverse cellular functions including neuronal activity (Albers, 1967; Post et al, 1972; Skou and Esmann, 1992). The β-subunit is known to be important for the correct folding and membrane localization of the αsubunit Both the β- and the FXYD (γ)- subunits have been shown to modulate Na+/K+-ATPase activity (Cornelius and Mahmmoud, 2003; Geering, 2008). Mutations in ATP1A3 have been linked to various neurological disorders, including rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). Familial RDP, wide spectrum of severity is associated with the same mutation

Objectives

Methods

Results

Conclusion