Expanding the Allelic and Clinical Heterogeneity of Movement Disorders Linked to Defects of Mitochondrial Adenosine Triphosphate Synthase

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F25%3A10498406" target="_blank" >RIV/00216208:11110/25:10498406 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00064165:_____/25:10498406

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=OBQOTKUclr" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=OBQOTKUclr</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/mds.30209" target="_blank" >10.1002/mds.30209</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Expanding the Allelic and Clinical Heterogeneity of Movement Disorders Linked to Defects of Mitochondrial Adenosine Triphosphate Synthase

Popis výsledku v původním jazyce

Background: Defects of mitochondrial ATP synthase (ATPase) represent an emerging, yet incompletely understood group of neurodevelopmental diseases with abnormal movements. Objective: The aim of this study was to redefine the phenotypic and mutational spectrum of movement disorders linked to the ATPase subunit-encoding genes ATP5F1A and ATP5F1B. Methods: We recruited regionally distant patients who had been genome or exome sequenced. Fibroblast cultures from two patients were established to perform RNA sequencing, immunoblotting, mass spectrometry-based high-throughput quantitative proteomics, and ATPase activity assays. In silico three-dimensional missense variant modeling was performed. Results: We identified a patient with developmental delay, myoclonic dystonia, and spasticity who carried a heterozygous frameshift c.1404del (p.Glu469Serfs*3) variant in ATP5F1A. The patient&apos;s cells exhibited significant reductions in ATP5F1A mRNA, underexpression of the α-subunit of ATPase in association with other aberrantly expressed ATPase components, and compromised ATPase activity. In addition, a novel deleterious heterozygous ATP5F1A missense c.1252G&gt;A (p.Gly418Arg) variant was discovered, shared by three patients from two families with hereditary spastic paraplegia (HSP). This variant mapped to a functionally important intersubunit communication site. A third heterozygous variant, c.1074+1G&gt;T, affected a canonical donor splice site of ATP5F1B and resulted in exon skipping with significantly diminished ATP5F1B mRNA levels, as well as impaired ATPase activity. The associated phenotype consisted of cerebral palsy (CP) with prominent generalized dystonia. Conclusions: Our data confirm and expand the role of dominant ATP5F1A and ATP5F1B variants in neurodevelopmental movement disorders. ATP5F1A/ATP5F1B-related ATPase diseases should be considered as a cause of dystonia, HSP, and CP. (C) 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Název v anglickém jazyce

Expanding the Allelic and Clinical Heterogeneity of Movement Disorders Linked to Defects of Mitochondrial Adenosine Triphosphate Synthase

Popis výsledku anglicky

Background: Defects of mitochondrial ATP synthase (ATPase) represent an emerging, yet incompletely understood group of neurodevelopmental diseases with abnormal movements. Objective: The aim of this study was to redefine the phenotypic and mutational spectrum of movement disorders linked to the ATPase subunit-encoding genes ATP5F1A and ATP5F1B. Methods: We recruited regionally distant patients who had been genome or exome sequenced. Fibroblast cultures from two patients were established to perform RNA sequencing, immunoblotting, mass spectrometry-based high-throughput quantitative proteomics, and ATPase activity assays. In silico three-dimensional missense variant modeling was performed. Results: We identified a patient with developmental delay, myoclonic dystonia, and spasticity who carried a heterozygous frameshift c.1404del (p.Glu469Serfs*3) variant in ATP5F1A. The patient&apos;s cells exhibited significant reductions in ATP5F1A mRNA, underexpression of the α-subunit of ATPase in association with other aberrantly expressed ATPase components, and compromised ATPase activity. In addition, a novel deleterious heterozygous ATP5F1A missense c.1252G&gt;A (p.Gly418Arg) variant was discovered, shared by three patients from two families with hereditary spastic paraplegia (HSP). This variant mapped to a functionally important intersubunit communication site. A third heterozygous variant, c.1074+1G&gt;T, affected a canonical donor splice site of ATP5F1B and resulted in exon skipping with significantly diminished ATP5F1B mRNA levels, as well as impaired ATPase activity. The associated phenotype consisted of cerebral palsy (CP) with prominent generalized dystonia. Conclusions: Our data confirm and expand the role of dominant ATP5F1A and ATP5F1B variants in neurodevelopmental movement disorders. ATP5F1A/ATP5F1B-related ATPase diseases should be considered as a cause of dystonia, HSP, and CP. (C) 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Movement Disorders

ISSN

0885-3185

e-ISSN

1531-8257

Svazek periodika

40

Číslo periodika v rámci svazku

7

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

1388-1400

Kód UT WoS článku

001476375600001

EID výsledku v databázi Scopus

2-s2.0-105003440095