Gemin5 Gene Mutation-Related Coenzyme Q10 Deficiency: Long-term Follow-up After Treatment

Background

Gemin5 is a highly conserved multifunctional protein that mainly functions in assembling small RNA-protein complexes in the cytoplasm and participates in the splicing process of pre-mRNA to generate mature mRNA. Previous studies have reported a series of patients carrying Gemin5 gene mutations showing abnormal neurological manifestations. However, there is currently no effective treatment for these Gemin5 mutation-related diseases.

In 2006, a study first discovered a patient with coenzyme Q10 (CoQ10) deficiency, and muscle biopsy results showed mitochondrial dysfunction. Subsequently, another patient with similar symptoms and CoQ10 deficiency was discovered, and both patients showed signs of symptom improvement after oral CoQ10 supplementation. However, there have been no clear reports on the direct association between Gemin5 and CoQ10 synthesis or mitochondrial function.

Research Source

This article was co-authored by Marivi V. Cascajo-Almenara, Natalia Juliá-Palacios, and several other researchers from institutions including the Carlos III Health Research Institute in Madrid, Spain, the Sant Joan de Déu Research Institute in Barcelona, and the University of Pittsburgh Medical Center in the United States. The paper was published in the European Journal of Human Genetics in 2024.

Research Process and Methods

Subjects and Methods

The study described three patients with Gemin5-related disease, two of whom (P1 and P2) received CoQ10 treatment, while the third patient (P3) did not receive treatment due to rapid early progression. The study conducted genetic analysis on patients and their family members through whole-exome sequencing (WES) and performed functional experiments in patient skin fibroblasts and Drosophila models.

Clinical Exploration

The two patients receiving CoQ10 treatment underwent neurological evaluations (ICARS and SARA scales) and neuroimaging studies (MRI). The research found that neuroimaging abnormalities persisted even with long-term CoQ10 supplementation. Clinical experiments included metabolic marker analysis, genomic DNA sequencing, protein expression determination, and transcriptome analysis.

Experimental Research

Skin Fibroblast Study

In this part of the study, it was found that CoQ10 content in patients’ fibroblasts was significantly lower than in normal controls, and supplementation with exogenous CoQ10 could restore intracellular CoQ10 levels. The experiment also found that mitochondrial oxygen consumption rate was reduced in fibroblasts of patients with Gemin5 gene mutations, and CoQ10 supplementation could partially or completely restore oxygen consumption rates.

Drosophila Model Study

In the Drosophila model, downregulation of the rigor mortis gene confirmed a decrease in CoQ10 levels, and CoQ10 supplementation could partially restore motor function and survival rates in flies.

Results

Clinical Results

Both treated patients showed improvement in clinical manifestations. Patient P1, who received continuous CoQ10 treatment for 20 years, showed no significant deterioration in cognitive function and maintained normal physical abilities. Patient P2 showed significant improvement in motor development after treatment and achieved independent walking at age 13. However, MRI still showed cerebellar atrophy and T2 hyperintensity in the dentate nucleus.

Experimental Results

Experimental results confirmed that CoQ10 synthesis was inhibited in fibroblasts and Drosophila models of Gemin5 mutation patients. CoQ10 supplementation could partially or completely restore mitochondrial function. Transcriptome analysis showed that genes related to CoQ10 synthesis were generally suppressed in patient cells, especially in patient P3.

Key Findings

This is the first discovery of an association between Gemin5 gene mutations and CoQ10 deficiency. Long-term CoQ10 supplementation treatment has shown significant clinical effects in improving patient symptoms without observable side effects.

Research Significance and Value

This study reveals a potential CoQ10 deficiency caused by Gemin5 gene mutations and provides a potential treatment method for this disease through oral CoQ10 supplementation. Although the research sample is limited and more clinical trials are needed to further validate these findings, preliminary results show the effectiveness of this treatment method and its great potential for improving patients’ quality of life.

Through this study, scientists have not only deepened their understanding of Gemin5 function but also provided new ideas and methods for treating related genetic diseases. The continuation and expansion of this research may lead to the development of a series of treatment options for similar diseases in the future.