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

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.