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Updated:25/05/2022 19:27h
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A malfunction in the mitochondria, the body’s so-called energy ‘factories’, can cause a variety of symptoms, including poor growth, fatigue and weakness, seizures, cognitive and developmental disabilities, and vision problems. The culprit could be a defect in any of the approximately 1,300 proteins that make up mitochondriabut scientists don’t know what many of these proteins do, making it difficult to identify the defective protein and treat the disease.
Now, researchers from the Washington University School of Medicine in St. Louis and the University of Wisconsin-Madison (USA) have revealed the functions of some of these mitochondrial proteins. And, thanks to this data, they have identified the genetic causes of three mitochondrial diseases.
The findings have been published in Nature.
“This study is an attempt to define the functions of some of the mitochondrial proteins in order to have a better understanding of what happens when they don’t function and, ultimately, a better chance of design targeted therapies to rectify those problems», says researcher David J. Pagliarini.
Mitochondrial diseases are a group of rare genetic pathologies that collectively affect one in 4,300 people. Since mitochondria provide energy to almost all cells, people with defects in their mitochondria can have symptoms anywhere in the body, although symptoms tend to be more pronounced in tissues that require more energy, such as the heart, brain and muscles.
Researchers have used CRISPR-Cas9 molecular scissors to remove individual genes of human cells. Thus, they generated a set of related cell lines, each derived from the same parent cell line but with a single gene deleted. The missing genes encoded 50 mitochondrial proteins of unknown function and 66 mitochondrial proteins with known functions.
After a series of analyses, they determined possible biological roles for many mitochondrial proteins of unknown function. And finally, were able to link three proteins to three mitochondrial pathologies separated.
One of these diseases is a multisystem disorder caused by defects in the main energy production pathway. the co-author Robert Taylor, from the University of Newcastle in Newcastle, UK, identified a patient with clear signs of the disorder but no mutations in the usual suspect genes. The researchers found a new gene in the pathway and showed that the patient carried a mutation.
Pagliarini’s team found that disruption of one gene, RAB5IF, eliminated a protein encoded by a different gene, TMCO1, which has been linked to cerebrofaciothoracic dysplasia, a pathology characterized by distinctive facial features and severe intellectual disability. The researchers showed that a mutation in RAB5IF was responsible for one case of cerebrofaciothoracic dysplasia and two cases of cleft lip in one family.
A third gene, when disrupted, caused problems with sugar storage, contributing to a syndrome fatal autoinflammatory.
“We focused mainly on these three diseases, but we found data connecting around 20 other proteins with biological pathways or processes,” says Pagliarini.
To help scientific research, experts have made the application available to the public MITOMICS that incorporates different easy-to-use analysis tools so that anyone can look for patterns and create charts with just one click. All data can be downloaded for further analysis.
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