Researchers found that a mutation in the USMG5 gene causes Leigh syndrome and deficient energy production in cells. This is the first evidence linking alterations in this gene to a human disease.
The study, “A splice-site mutation in USMG5 causes Leigh Syndrome due to lack of ATP synthesis (P2.085),” will be presented as a poster at the 2018 American Academy of Neurology (AAN) Annual Meeting, which will take place between April 21-27, in Los Angeles.
The presentation will be held on Monday, April 23, at 5:30 PM PST, as part of the P2 – Poster Session II “Child Neurology and Developmental Neurology ePoster Session.” The study’s abstract was recently published in the journal Neurology.
Leigh syndrome is a progressive neurological disorder and the most common pediatric form of mitochondrial disease. Symptoms usually appear between the ages of 3 months and 2 years, and consist of gradual loss of mental and movement abilities, with subsequent respiratory failure.
The syndrome has been associated with mutations in more than 70 genes, most of which are involved in energy production in mitochondria, the cell’s power plant. Mitochondria produce energy via generation of a molecule called adenosine triphosphate (ATP).
Mutations in genes regulating the structure and assembly of the enzyme ATP synthase have been commonly linked with Leigh syndrome. However, mutations in the USMG5 gene, which codes for a protein required for ATP synthase function, have never previously been shown in any human disease.
The researchers described the case of a 2-year old Leigh syndrome patient with a homozygous mutation in USMG5. Homozygous mutations are genetic alterations in both gene copies inherited from parents. This mutation was of the splice-site type, which refers to changes at the frontier between an exon and an intron in the DNA sequence. Exons are the gene portions that generate proteins, while introns are taken out during gene expression.
The scientists conducted functional assays in the patient’s fibroblasts, the most common cells in connective tissue. ATP production was evaluated through analytical methods. The investigators then confirmed the mutation’s impact on energy production by inserting normal (“wild-type”) USMG5 gene in the patient’s fibroblasts and measuring the activity of ATP synthase.
Results from the experiments in the child’s fibroblasts revealed reduced levels of ATP synthase and ATP. Transferring normal USMG5 gene to the patient’s cells increased ATP synthase level and restored the rate of ATP production.
“We here demonstrate that a novel variant in USMG5 causes Leigh syndrome,” the researchers wrote.
“The identification of defects in ATP synthase levels and ATP production in the patient’s fibroblasts indicates that USMG5 plays a critical role in cell mitochondrial energy homeostasis [normal behavior],” they added.