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

NEUROBIOLOGY OF DISEASE

卷:143

Article

Lazarov, Elinor¹  Hillebrand, Merle¹  Schroeder, Simone¹  Ternka, Katharina¹  Hofhuis, Julia¹  Ohlenbusch, Andreas¹  Barrantes-Freer, Alonso²  Pardo, Luis A.³  Fruergaard, Marlene U.⁴  Nissen, Poul⁴  Brockmann, Knut¹  Gaertner, Jutta¹  Rosewich, Hendrik¹ 

[1] Georg August Univ, Univ Med Ctr Gottingen, Dept Pediat & Adolescent Med, Div Pediat Neurol, Gottingen, Germany

[2] Univ Med Ctr, Inst Neuropathol, Gottingen, Germany

[3] Max Planck Inst Expt Med, Dept Mol Biol Neuronal Signals, Gottingen, Germany

[4] Aarhus Univ, Dept Mol Biol & Genet, DANDRITE Nord EMBL Partnership Mol Med, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark

关键词: Parkinsonism;    Alternating hemiplegia of childhood;    AHC;    Rapid-onset dystonia-parkinsonism;    RDP;    ATP1A3;    P-type ATPase;    Na+/K+-ATPase alpha 3 subunit;    Movement disorder;   

DOI  :  10.1016/j.nbd.2020.105012

来源: Elsevier

【 摘 要 】

Heterozygous mutations in the ATP1A3 gene, coding for an alpha subunit isoform (alpha 3) 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 alpha 3 subunit. Here we compared the effect of twelve different RDP and AHC specific mutations on the expression and function of the alpha 3 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.