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Mutations of GEMIN5 are associated with coenzyme Q10 deficiency: long-term follow-up after treatment

European Journal of Human Genetics volume 32, pages 426–434 (2024)Cite this article

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Abstract

GEMIN5 exerts key biological functions regulating pre-mRNAs intron removal to generate mature mRNAs. A series of patients were reported harboring mutations in GEMIN5. No treatments are currently available for this disease. We treated two of these patients with oral Coenzyme Q10 (CoQ10), which resulted in neurological improvements, although MRI abnormalities remained. Whole Exome Sequencing demonstrated compound heterozygosity at the GEMIN5 gene in both cases: Case one: p.Lys742* and p.Arg1016Cys; Case two: p.Arg1016Cys and p.Ser411Hisfs*6. Functional studies in fibroblasts revealed a decrease in CoQ10 biosynthesis compared to controls. Supplementation with exogenous CoQ10 restored it to control intracellular CoQ10 levels. Mitochondrial function was compromised, as indicated by the decrease in oxygen consumption, restored by CoQ10 supplementation. Transcriptomic analysis of GEMIN5 patients compared with controls showed general repression of genes involved in CoQ10 biosynthesis. In the rigor mortis defective flies, CoQ10 levels were decreased, and CoQ10 supplementation led to an improvement in the adult climbing assay performance, a reduction in the number of motionless flies, and partial restoration of survival. Overall, we report the association between GEMIN5 dysfunction and CoQ10 deficiency for the first time. This association opens the possibility of oral CoQ10 therapy, which is safe and has no observed side effects after long-term therapy.

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Fig. 1: Total amount and rate of CoQ10 synthesis in GEMIN5 patients’ fibroblasts.
Fig. 2: Respiratory defects in patients’ fibroblasts.
Fig. 3: COQs and MRC complexes’ protein levels in fibroblasts.
Fig. 4: Effect of CoQ10 supplementation in CoQ levels in rigor mortis adult flies.

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Data availability

Data about the basic research experiments are available upon reasonable request.

Code availability

Some of the data generated or analyzed during this study can be found within the published article and its supplementary files. Data of WES from patients is available from the corresponding author upon reasonable request.

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Acknowledgements

We are indebted to the patients and families with GEMIN5 mutations.

Funding

This research was funded by Instituto de Salud Carlos III (PI20-00340 and PI20/00541) (co-funded by European Regional Development Fund “A way to make Europe”), the Centre for Biomedical Research on Rare Diseases (CIBERER), the U.S. National Institute of Health (NIH), the National Institute of Neurological Disorders and Stroke (NINDS) R01NS134215 and Carmen de Torres grants (Institut de Recerca Sant Joan de Déu). CIBERER is an initiative from the Health Institute Carlos III.

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Author notes

  1. These authors contributed equally: Marivi V. Cascajo-Almenara, Natalia. Juliá-Palacios.

  2. These authors jointly supervised this work: Udai Pandey, Carlos Santos-Ocaña, Rafael Artuch.

Authors and Affiliations

  1. Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain

    Marivi V. Cascajo-Almenara, Roser Urreizti, Ana Sánchez-Cuesta, Daniel M. Fernández-Ayala, Andres Nascimento, Francesc Palau, Delia Yubero, Angels García-Cazorla, Carlos Santos-Ocaña & Rafael Artuch

  2. Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain

    Natalia. Juliá-Palacios, Roser Urreizti, Clara Oliva, Maria del Mar O´Callaghan, Jordi Muchart, Andres Nascimento, Carlos I. Ortez, Daniel Natera-de Benito, Mercedes Pineda, Noelia Rivera, Francesc Palau, Delia Yubero, Angels García-Cazorla & Rafael Artuch

  3. Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide, 41013, Sevilla, Spain

    Elena García-Díaz, Plácido Navas & Carlos Santos-Ocaña

  4. Division of Inborn Errors of Metabolism-IBC, Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, 08028, Barcelona, Spain

    Abraham J. Paredes-Fuentes

  5. Internal Medicine Department, Clinic Hospital and University of Barcelona, 08036, Barcelona, Spain

    Pedro J. Moreno-Lozano

  6. Department of Pediatrics, Childrens Hospital of Pittsburgh and Children’s Neuroscience Institute, University of Pittsburgh Medical Center and Children’s Hospital of Pittsburgh, 15224, Pittsburgh, PA, USA

    Tyler R. Fortuna, Deepa S. Rajan & Udai Bhan Pandey

  7. Clinical Genetics Unit, Department of Women and Children’s Health, Padua University, 35128, Padua, Italy

    Leonardo Salviati

  8. Division of Pediatrics, Faculty of Medicine and Health Sciences, University of Barcelona, 08036, Barcelona, Spain

    Francesc Palau

Authors
  1. Marivi V. Cascajo-Almenara
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Contributions

All authors critically reviewed the manuscript. RA, CSO, AGC, UP, and PN contributed to the experimental design. NJP, NR, MdMOC, PJML, CIO, JM, AN, DNdB, DSR and MP contributed to the clinical data collection, analysis, and evaluation. RU, DY, FP. performed the genetic data analysis. MVCA, ASC, DMFA, EGD, CO, AJPF, CSO, PN, RU, LS, TRF, and NJP conducting experiments, acquiring data, analyzing data, providing reagents. RA, CSO, NJP, RU, CO, MVCA drafted the manuscript and elaborated the main figures and tables.

Corresponding authors

Correspondence to Udai Bhan Pandey, Carlos Santos-Ocaña or Rafael Artuch.

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Competing interests

The authors declare no competing interests.

Ethical approval

All patients provided the informed consent for the genetic studies and skin biopsies collection. For supplementary videos, consent from patient 1 (P1) was obtained. For patient 2 (P2), the family refused to provide informed consent to publish the video. The study was conducted following the Declaration of Helsinki, and the ethical committee of the institution of Sant Joan de Déu Hospital has approved it.

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Cascajo-Almenara, M.V., Juliá-Palacios, N., Urreizti, R. et al. Mutations of GEMIN5 are associated with coenzyme Q10 deficiency: long-term follow-up after treatment. Eur J Hum Genet 32, 426–434 (2024). https://doi.org/10.1038/s41431-023-01526-2

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