Harrer Philip, Krygier Magdalena, Krenn Martin, Kittke Volker, Danis Martin, Krastev Georgi, Saparov Alice, Pichon Virginie, Malbos Marlène, Scherer Clarisse, Dzinovic Ivana, Skorvanek Matej, Kopajtich Robert, Prokisch Holger, Silvaieh Sara, Grisold Anna, Mazurkiewicz-Bełdzińska Maria, de Sainte Agathe Jean-Madeleine, Winkelmann Juliane, Necpal Jan, Jech Robert, Zech Michael
Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich, Germany.
Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
Mov Disord. 2025 Jul;40(7):1388-1400. doi: 10.1002/mds.30209. Epub 2025 Apr 25.
Defects of mitochondrial ATP synthase (ATPase) represent an emerging, yet incompletely understood group of neurodevelopmental diseases with abnormal movements.
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.
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.
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'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>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>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.
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. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
线粒体ATP合酶（ATPase）缺陷代表了一组新出现但尚未完全理解的伴有异常运动的神经发育疾病。
本研究的目的是重新定义与ATPase亚基编码基因ATP5F1A和ATP5F1B相关的运动障碍的表型和突变谱。
我们招募了经过全基因组或外显子组测序的来自不同地区的患者。建立了两名患者的成纤维细胞培养物，以进行RNA测序、免疫印迹、基于质谱的高通量定量蛋白质组学和ATPase活性测定。进行了计算机三维错义变异建模。
我们鉴定出一名患有发育迟缓、肌阵挛性肌张力障碍和痉挛的患者，其ATP5F1A基因携带杂合移码c.1404del（p.Glu469Serfs*3）变异。该患者的细胞表现出ATP5F1A mRNA显著减少，ATPaseα亚基表达不足，并伴有其他异常表达的ATPase成分，且ATPase活性受损。此外，还发现了一种新的有害杂合ATP5F1A错义c.1252G>A（p.Gly418Arg）变异，来自两个患有遗传性痉挛性截瘫（HSP）家族的三名患者携带该变异。该变异位于一个功能重要的亚基间通讯位点。第三个杂合变异c.1074+1G>T影响了ATP5F1B的一个典型供体剪接位点，导致外显子跳跃，ATP5F1B mRNA水平显著降低，ATPase活性受损。相关表型为伴有明显全身性肌张力障碍的脑性瘫痪（CP）。
我们的数据证实并扩展了显性ATP5F1A和ATP5F1B变异在神经发育性运动障碍中的作用。应将ATP5F1A/ATP5F1B相关的ATPase疾病视为肌张力障碍、HSP和CP的一个病因。©2025作者。由Wiley Periodicals LLC代表国际帕金森和运动障碍协会出版的《运动障碍》。
