Mutations of GEMIN5 are associated with coenzyme Q 10 deficiency: long-term follow-up after treatment

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 Q (CoQ ), which resulted...

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Published inEuropean journal of human genetics : EJHG Vol. 32; no. 4; p. 426
Main Authors Cascajo-Almenara, Marivi V, Juliá-Palacios, Natalia, Urreizti, Roser, Sánchez-Cuesta, Ana, Fernández-Ayala, Daniel M, García-Díaz, Elena, Oliva, Clara, O Callaghan, Maria Del Mar, Paredes-Fuentes, Abraham J, Moreno-Lozano, Pedro J, Muchart, Jordi, Nascimento, Andres, Ortez, Carlos I, Natera-de Benito, Daniel, Pineda, Mercedes, Rivera, Noelia, Fortuna, Tyler R, Rajan, Deepa S, Navas, Plácido, Salviati, Leonardo, Palau, Francesc, Yubero, Delia, García-Cazorla, Angels, Pandey, Udai Bhan, Santos-Ocaña, Carlos, Artuch, Rafael
Format Journal Article
LanguageEnglish
Published England 01.04.2024
Subjects
Adult
Ataxia
Follow-Up Studies
Humans
Mitochondrial Diseases - drug therapy
Mitochondrial Diseases - genetics
Muscle Weakness
Mutation
SMN Complex Proteins - genetics
Ubiquinone - deficiency
Ubiquinone - genetics
Ubiquinone - metabolism
Ubiquinone - therapeutic use
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Summary: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 Q (CoQ ), 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 CoQ biosynthesis compared to controls. Supplementation with exogenous CoQ restored it to control intracellular CoQ levels. Mitochondrial function was compromised, as indicated by the decrease in oxygen consumption, restored by CoQ supplementation. Transcriptomic analysis of GEMIN5 patients compared with controls showed general repression of genes involved in CoQ biosynthesis. In the rigor mortis defective flies, CoQ levels were decreased, and CoQ 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 CoQ deficiency for the first time. This association opens the possibility of oral CoQ therapy, which is safe and has no observed side effects after long-term therapy.
ISSN:1476-5438