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

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  • Elinor Lazarov, Georg-August-University
  • ,
  • Merle Hillebrand, Georg-August-University
  • ,
  • Simone Schröder, Georg-August-University
  • ,
  • Katharina Ternka, Georg-August-University
  • ,
  • Julia Hofhuis, Georg-August-University
  • ,
  • Andreas Ohlenbusch, Georg-August-University
  • ,
  • Alonso Barrantes-Freer, University of Göttingen
  • ,
  • Luis A. Pardo, Max Planck Institute of Experimental Medicine
  • ,
  • Marlene U. Fruergaard
  • Poul Nissen
  • Knut Brockmann, Georg-August-University
  • ,
  • Jutta Gärtner, Georg-August-University
  • ,
  • Hendrik Rosewich, Georg-August-University

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.

Original languageEnglish
Article number105012
JournalNeurobiology of Disease
Number of pages9
Publication statusPublished - Sept 2020

    Research areas

  • AHC, Alternating hemiplegia of childhood, ATP1A3, Movement disorder, Na/K-ATPase alpha 3 subunit, P-type ATPase, Parkinsonism, Rapid-onset dystonia-parkinsonism, RDP, Na+/K+-ATPase alpha 3 subunit, K+-ATPASE, CRYSTAL-STRUCTURE, NA,K-ATPASE, INTRACELLULAR NA+, CELL-DEATH, NA+,K+-ATPASE ACTIVITY, DE-NOVO MUTATIONS, SODIUM-PUMP, AFFINITY, ALPHA-3 ISOFORM

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