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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.
Neurobiol Dis. 2020 Sep; 143:105012.ND

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.

Authors+Show Affiliations

University Medical Center Göttingen, Georg August University, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Germany. Electronic address: elinor.lazarov@med.uni-goettingen.de.University Medical Center Göttingen, Georg August University, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Germany. Electronic address: hillebrandmerle@gmail.com.University Medical Center Göttingen, Georg August University, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Germany. Electronic address: simone.schroeder@med.uni-goettingen.de.University Medical Center Göttingen, Georg August University, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Germany. Electronic address: katharina.ternka@med.uni-goettingen.de.University Medical Center Göttingen, Georg August University, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Germany. Electronic address: julia.hofhuis@med.uni-goettingen.de.University Medical Center Göttingen, Georg August University, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Germany. Electronic address: aohlenb@gwdg.de.Institute of Neuropathology, University Medical Centre, Göttingen, Germany. Electronic address: alonso.barrantes-freer@medizin.uni-leipzig.de.Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Göttingen, Germany. Electronic address: pardo@em.mpg.de.DANDRITE - Nordic EMBL Partnership for Molecular Medicine, Dept. Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark. Electronic address: marlenef@mbg.au.dk.DANDRITE - Nordic EMBL Partnership for Molecular Medicine, Dept. Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark. Electronic address: pn@mbg.au.dk.University Medical Center Göttingen, Georg August University, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Germany. Electronic address: kbrock@med.uni-goettingen.de.University Medical Center Göttingen, Georg August University, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Germany. Electronic address: gaertnj@med.uni-goettingen.de.University Medical Center Göttingen, Georg August University, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Germany. Electronic address: hendrik.rosewich@med.uni-goettingen.de.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32653672

Citation

Lazarov, Elinor, et al. "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, vol. 143, 2020, p. 105012.
Lazarov E, Hillebrand M, Schröder S, et al. Comparative analysis of alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism ATP1A3 mutations reveals functional deficits, which do not correlate with disease severity. Neurobiol Dis. 2020;143:105012.
Lazarov, E., Hillebrand, M., Schröder, S., Ternka, K., Hofhuis, J., Ohlenbusch, A., Barrantes-Freer, A., Pardo, L. A., Fruergaard, M. U., Nissen, P., Brockmann, K., Gärtner, J., & Rosewich, H. (2020). 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, 143, 105012. https://doi.org/10.1016/j.nbd.2020.105012
Lazarov E, et al. Comparative Analysis of Alternating Hemiplegia of Childhood and Rapid-onset Dystonia-parkinsonism ATP1A3 Mutations Reveals Functional Deficits, Which Do Not Correlate With Disease Severity. Neurobiol Dis. 2020;143:105012. PubMed PMID: 32653672.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparative analysis of alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism ATP1A3 mutations reveals functional deficits, which do not correlate with disease severity. AU - Lazarov,Elinor, AU - Hillebrand,Merle, AU - Schröder,Simone, AU - Ternka,Katharina, AU - Hofhuis,Julia, AU - Ohlenbusch,Andreas, AU - Barrantes-Freer,Alonso, AU - Pardo,Luis A, AU - Fruergaard,Marlene U, AU - Nissen,Poul, AU - Brockmann,Knut, AU - Gärtner,Jutta, AU - Rosewich,Hendrik, Y1 - 2020/07/10/ PY - 2020/02/18/received PY - 2020/06/12/revised PY - 2020/07/07/accepted PY - 2020/7/13/pubmed PY - 2020/7/13/medline PY - 2020/7/13/entrez KW - AHC KW - ATP1A3 KW - Alternating hemiplegia of childhood KW - Movement disorder KW - Na(+)/K(+)-ATPase alpha 3 subunit KW - P-type ATPase KW - Parkinsonism KW - RDP KW - Rapid-onset dystonia-parkinsonism SP - 105012 EP - 105012 JF - Neurobiology of disease JO - Neurobiol. Dis. VL - 143 N2 - 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. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/32653672/Comparative_analysis_of_alternating_hemiplegia_of_childhood_and_rapid-onset_dystonia-parkinsonism_ATP1A3_mutations_reveals_functional_deficits,_which_do_not_correlate_with_disease_severity L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(20)30287-4 DB - PRIME DP - Unbound Medicine ER -
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