Biallelic Variants in Cause a Severe Infantile Metabolic Disorder Affecting Mitochondrial Function.

Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (; previously called ) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of has been unclear, and little is known of the protein's precise biological function. In the present paper, we report biallelic variants in identified by genome sequencing in a patient with suspected mitochondrial disease. The child presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, and received rapid genomic testing. He died shortly after. Magnetic resonance imaging (MRI) brain imaging showed changes resembling Leigh syndrome, one of the more common childhood mitochondrial neurological diseases. Functional studies in patient fibroblasts showed a heightened sensitivity to mitochondrial metabolic stress and increased mitochondrial superoxide levels. Quantitative proteomic analysis demonstrated decreased levels of subunits of the mitochondrial respiratory chain complex I, and both the small and large subunits of the mitochondrial ribosome, suggesting a mitoribosomal defect. Our findings support the critical role of in human cells, and suggest that the biallelic variants are associated with mitochondrial dysfunction, and can plausibly explain the child's clinical presentation.