Abstract
Objective: To describe a patient with a homozygous splice-site mutation in USMG5, a protein required for ATP synthase function
Background: Leigh syndrome, the most common pediatric presentation of mitochondrial disease, is characterized by progressive encephalopathy. Leigh syndrome has been linked to mutations in more than 70 genes, most of which are required for mitochondrial energy metabolism. Mitochondria produce energy through the oxidation of substrates and generation of ATP. Mutations in structural and assembly genes for complex V (ATP synthase) have been frequently associated with Leigh syndrome. Defect in USMG5 have never been linked to human diseases
Design/Methods: A homozygous mutation in USMG5 was detected by whole exome sequencing. The mutation was validated by functional assays in patient’s fibroblasts. High-performance liquid chromatography (HPLC) was used to study cell ATP production. To confirm the pathogenicity of the mutation, genetic rescue of the biochemical phenotype was performed by transfecting patient’s fibroblasts with wild type human USMG5
Results: Here we describe a 2-year-old boy with Leigh syndrome. Whole exome sequencing revealed a homozygous splice-site mutation in USMG5. Studies conducted in patient’s fibroblasts revealed altered ATP synthase levels and reduced ATP synthesis despite the normal activities of mitochondrial respiratory chain enzymes. Genetic rescue of USMG5 demonstrated increase ATP synthase and recovery of ATP synthesis rate.
Conclusions: We here demonstrate that a novel variant in USMG5 causes Leigh syndrome. 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.
Disclosure: Dr. Barca has nothing to disclose. Dr. Juanola-Falgarona has nothing to disclose. Dr. Emmanuele has nothing to disclose. Dr. Tadesse has nothing to disclose. Dr. Ziosi has nothing to disclose. Dr. Akman has nothing to disclose. Dr. Tanji has nothing to disclose. Dr. Chung has nothing to disclose. Dr. Hirano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Meves Pharmaceuticals Inc., Stealth BioTherapeutics Inc, and Sarepta Therapeutics Inc.
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