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 ₁₀ (CoQ ₁₀ ), 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 ₁₀ biosynthesis compared to controls. Supplementation with exogenous CoQ ₁₀ restored it to control intracellular CoQ ₁₀ levels. Mitochondrial function was compromised, as indicated by the decrease in oxygen consumption, restored by CoQ ₁₀ supplementation. Transcriptomic analysis of GEMIN5 patients compared with controls showed general repression of genes involved in CoQ ₁₀ biosynthesis. In the rigor mortis defective flies, CoQ ₁₀ levels were decreased, and CoQ ₁₀ 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 ₁₀ deficiency for the first time. This association opens the possibility of oral CoQ ₁₀ therapy, which is safe and has no observed side effects after long-term therapy.
(© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)