Loss-of-function variant of SLC27A3 causes mitochondrial dysfunction and a metabolic neurodevelopmental disorder via...

Inborn errors of metabolism (IEMs) lead to early-onset neurodegenerative disorders often caused by mitochondrial dysfunction. In this study, we identified a homozygous frameshift mutation (c.283dupG; p.Cys65LeufsTer13) in SLC27A3, identified through exome sequencing in a 2-month-old female proband presenting with developmental regression, hypotonia, seizure, feeding difficulty, and bilateral putaminal lesions on brain magnetic resonance imaging (MRI). The mutation results in a truncated, non-functional protein and complete loss of SLC27A3 expression in proband-derived fibroblasts. Results show the absence of SLC27A3 and aberrant mitochondrial morphology with clumped networks. Metabolic profiling showed elevated acyl-carnitine levels in the cytosol of proband cells, indicative of disrupted fatty acid oxidation. Additionally, mitochondrial respiratory chain activity was significantly reduced, and flow cytometry revealed increased cell death in mutant cells compared to controls. Protein-protein interaction analysis revealed SLC27A3 networks linked to fatty acid metabolism, ER-associated degradation (ERAD), and ion transport. GO enrichment demonstrated strong associations with transporter activity, protein homeostasis, and ER-mitochondrial membrane networks. Regional expression profiling showed high SLC27A3 transcript levels in the basal ganglia, correlating with the observed neuropathology. These findings position SLC27A3 as a critical lipid transporter involved in neuronal energy metabolism and proteostasis, and implicate its loss in mitochondrial encephalopathy. This study expands the genotypic and phenotypic spectrum of metabolic neurodevelopmental disorders and highlights the importance of fatty acid transport proteins in mitochondrial health and brain development. Our findings propose SLC27A3 as a novel candidate gene for early-onset mitochondrial disorders.