The FBXL4 gene encodes F-Box and Leucine-Rich Repeat Protein 4, a protein localized to the mitochondrial intermembrane space. As the name suggests, the protein contains an F box at its N-terminal, followed by 11 leucine rich repeats. The F-box is an approximately 40 amino acid motif that is involved in the mediation of protein-protein interactions and binds directly to S-phase kinase-associated protein 1 (SKP1). Members of the F-box family of proteins constitute one component of the modular E3 ubiquitin protein ligases. These complexes are also known as SCFs (SKP1, cullin, F-box proteins) and function in phosphorylation dependent ubiquitination.
Defects in FBXL4 are associated with Mitochondrial DNA Depletion Syndrome 13 (Encephalomyopathic Type), (MTDPS13), an often fatal, infantile-onset disorder. It is caused by defects in mitochondrial oxidative phosphorylation and decreased mtDNA content. The disease is characterized by encephalopathy, severe global developmental delay, cerebral atrophy, white matter abnormalities, facial dysmorphia, hypotonia and lactic acidosis. Expression of wildtype FBXL4 in the cells of individuals affected by MTDPS13 results in the rescue of mitochondrial biochemical defects and mtDNA depletion.