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New genetic variant responsible for severe coenzyme Q deficiency identified

A CABD research group discovers a variant in the COQ4 gene that affects cellular energy production.

The study highlights the importance of analyzing non-coding DNA regions in undiagnosed diseases.

Rare diseases affect millions of people worldwide, but their diagnosis remains a challenge due to their low prevalence and lack of knowledge about their genetic causes. A research team from the Andalusian Center for Developmental Biology (CABD) has managed to identify and validate a new genetic variant in the COQ4 gene, responsible for a severe deficiency of coenzyme Q (CoQ), a lipid essential for energy production in our cells.

This finding, published in the journal Molecular Genetics and Metabolism Reports, not only expands knowledge about these mitochondrial diseases, but also highlights the need to analyze regions of DNA that are not traditionally studied in standard genetic analyses.

A difficult diagnosis for a devastating disease

The study focuses on the case of a patient who died at 16 months of age without an accurate diagnosis, despite presenting symptoms compatible with a mitochondrial disease. Although an exome analysis, a technique that studies only the coding regions of DNA, was performed on her, the results did not provide a clear explanation for her disease.

However, further analysis detected a change in an intronic region of the COQ4 gene. Although this area of the DNA does not directly encode proteins, the mutation altered the maturation process of the messenger RNA, resulting in a drastic reduction in the amount of functional protein produced by one of the gene's alleles.

The other allele of COQ4 exhibited a previously described change that generated a truncated and non-functional protein. As a consequence, the patient did not produce enough COQ4 protein, which affected the synthesis of coenzyme Q, a molecule essential for the functioning of the mitochondrial electron transport chain and cellular energy production. This energy deficiency had severe clinical consequences and ultimately resulted in a fatal outcome.

This study has allowed us to expand the catalog of pathogenic variants of COQ4 and reinforces the importance of investigating non-coding regions of DNA, which could be key in many cases of undiagnosed rare diseases”, says Gloria Brea, professor of the Cell Biology Area of the Pablo de Olavide University and principal investigator of the group 'Molecular basis of Coenzyme Q deficiency and developmental bioenergetics' of the CABD, a joint center of the Spanish National Research Council (CSIC), the Pablo de Olavide University and the Andalusian Regional Government.



The lead author of the work, Gloria Brea Calvo

The value of a diagnosis: relief and hope for families

Since 2015, when the research team participated in identifying the first cases of pathogenic variants in COQ4, only a few dozen patients have been described worldwide with this primary coenzyme Q deficiency.

The patient's diagnosis, although late for possible treatment, had a profound impact on her family. “In rare diseases, access to a diagnosis can take up to five years on average, which generates uncertainty, anxiety and difficulties in accessing specific care. Knowing with certainty what caused their daughter's disease allowed the parents to close a stage of uncertainty and, in addition, to make informed decisions about their future,” explains the UPO researcher.

Thanks to the molecular diagnosis, the family was able to access appropriate genetic counseling, which enabled them to have two healthy children. For them, this breakthrough meant a radical change in their lives, preventing the disease from affecting their offspring again.

“This case highlights a common reality in the field of minority diseases: each diagnosis is a victory, not only for the scientific community, but also for the families seeking answers,” states María Alcázar-Fabra, first author of the study.


María Alcázar-Fabra, this work is part of her PhD thesis

A promising future: animal models and new therapeutic strategies

The research team has been studying primary coenzyme Q deficiencies and working on their molecular diagnosis for years. However, due to the low prevalence of the disease, it is difficult to obtain sufficient clinical data to advance our understanding and treatment.

To overcome this limitation, the group has obtained government funding to develop zebrafish models that carry the mutations identified in patients. These models will allow the disease to be studied from its early stages of development, shedding light on how it originates and progresses.

In addition, these models will serve as a platform for drug screening, which could open the door to new therapeutic strategies. Although there is currently no effective treatment for coenzyme Q deficiency caused by mutations in COQ4, the possibility of testing different compounds in an animal model will accelerate the search for solutions.

“This work not only expands our knowledge of rare mitochondrial diseases, but also underlines the importance of research in genetics and the impact it can have on the lives of patients and their families,” states Gloria Brea.

Alcázar-Fabra et al. Identification of a new COQ4 spliceogenic variant causing severe primary coenzyme Q deficiency, Molecular Genetics and Metabolism Reports 42 (2025). https://doi.org/10.1016/j.ymgmr.2024.101176