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. 2024 Apr;32(4):426-434.
doi: 10.1038/s41431-023-01526-2. Epub 2024 Feb 5.

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

Marivi V Cascajo-Almenara #  1 , Natalia Juliá-Palacios #  2 , Roser Urreizti  1   2 , Ana Sánchez-Cuesta  1 , Daniel M Fernández-Ayala  1 , Elena García-Díaz  3 , Clara Oliva  2 , Maria Del Mar O Callaghan  2 , Abraham J Paredes-Fuentes  4 , Pedro J Moreno-Lozano  5 , Jordi Muchart  2 , Andres Nascimento  1   2 , Carlos I Ortez  2 , Daniel Natera-de Benito  2 , Mercedes Pineda  2 , Noelia Rivera  2 , Tyler R Fortuna  6 , Deepa S Rajan  6 , Plácido Navas  3 , Leonardo Salviati  7 , Francesc Palau  1   2   8 , Delia Yubero  1   2 , Angels García-Cazorla  1   2 , Udai Bhan Pandey  9 , Carlos Santos-Ocaña  10   11 , Rafael Artuch  12   13
Affiliations

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

Marivi V Cascajo-Almenara et al. Eur J Hum Genet. 2024 Apr.

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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Conflict of interest statement

The authors declare no competing interests.

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