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Homozygous COQ9 mutation: a new cause of potentially treatable hereditary spastic paraplegia

European Journal of Human Genetics (2025)Cite this article

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Abstract

Primary Coenzyme Q10 (CoQ10) deficiencies are a group of clinically heterogenous mitochondrial disorders that result from defects in CoQ10 biosynthesis. Their diagnosis is complicated by the absence of pathognomonic signs and poor genotype-phenotype correlations. Pathogenic variants in the COQ9 gene are a rare cause of CoQ10 deficiency: few cases have been reported, and the clinical presentation was described as a very severe multisystemic disorder with neonatal onset, ultimately leading to premature death. Through exome sequencing, we identified a novel homozygous splicing variant c.73 G > A in the COQ9 gene (NG_027696.1, NM_020312.4) in two adult siblings who presented with pure spastic paraplegia with onset in childhood. mRNA analysis from different tissues of one of the siblings revealed that this variant alters COQ9 splicing, resulting in undetectable levels of COQ9 and COQ7 proteins and reduced concentrations of CoQ10 in muscle and fibroblasts. Additionally, the accumulation of 6-demethoxycoenzyme Q10, the substrate of COQ7, was observed in both plasma and fibroblasts. Furthermore, fibroblast proliferation rate was reduced when enhancing the mitochondrial metabolism by replacing glucose with galactose in the culture medium, and was rescued by the addition of exogenous CoQ10, suggesting a therapeutic avenue for these patients. Altogether, we report here the first example of hereditary spastic paraplegia related to a mutation of the COQ9 gene that expands the spectrum of clinical manifestations and opens new therapeutic opportunities.

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Fig. 1
Fig. 2: COQ9 c.73 G > A variation affects COQ9 splicing and decreases COQ9 and COQ7 protein level in the patients’ tissues.
Fig. 3: Representative HPLC-MS/MS chromatograms for the detection of CoQ10 and 6-DMQ.
Fig. 4: CoQ10 deficiency lowers cell proliferation but can be rescued by exogenous CoQ10.

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Data availability

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

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Funding

This research received no external funding.

Author information

Authors and Affiliations

  1. Department of Biochemistry, University Hospital of Caen, Caen, France

    Fanny Fontaine & Stéphane Allouche

  2. Physiopathology and Imaging of Neurological Disorders, UMRS 1237, University of Caen Normandie, Caen, France

    Fanny Fontaine & Stéphane Allouche

  3. Department of Genetics, Hospices Civils de Lyon, Groupement Est, Bron, France

    Audrey Labalme & Gaëtan Lesca

  4. Department of Neurology, Hôpital Pierre Wertheimer, Hospices Civils de Lyon Groupement Est, Bron, France

    Chloé Laurencin

  5. Department of Electroneuromyography and Neuromuscular Pathologies, Hôpital Pierre Wertheimer, Hospices Civils de Lyon Groupement Est, Bron, France

    Julian Theuriet

  6. Pathophysiology and Genetics of Neuron and Muscle, CNRS UMR 5261, INSERM U1315, University of Lyon 1, Faculté de Médecine Lyon Est, Lyon, France

    Julian Theuriet, Arnaud Jacquier, Nicolas Lacoste & Gaëtan Lesca

  7. Centre de Biotechnologie Cellulaire, Hospices Civils de Lyon Groupement Est, Bron, France

    Arnaud Jacquier

  8. Department of Neuropathology, Hôpital Pierre Wertheimer, Hospices Civils de Lyon Groupement Est, Bron, France

    Nathalie Streichenberger

  9. Institut NeuroMyogène, CNRS UMR 5261, INSERM U1315, University of Lyon 1, Faculté de Médecine Lyon Est, Lyon, France

    Nathalie Streichenberger

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  1. Fanny Fontaine
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Contributions

Writing – original draft, F.F.; writing – review & editing, S.A., G.L., F.F., A.J., J.T.; conceptualization, G.L., S.A., F.F., A.J., J.T.; formal analysis, S.A., A.J.; methodology, G.L., S.A., F.F., A.J., J.T.; investigation – in vitro and variant analysis, F.F., A.L., J.T., A.J., N.L., N.S.; investigation – clinical, C.L.; visualization, F.F., A.J.; supervision, S.A., G.L.

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Correspondence to Stéphane Allouche.

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All procedures performed in this study involving human participants were carried out in accordance with the ethical standards of the University Hospital of Caen, and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from both patients included in the study.

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Fontaine, F., Labalme, A., Laurencin, C. et al. Homozygous COQ9 mutation: a new cause of potentially treatable hereditary spastic paraplegia. Eur J Hum Genet (2025). https://doi.org/10.1038/s41431-025-01895-w

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