Mitochondrial Complex V Deficiency Caused by a Homozygous Splice Variant in ATP5PO

Most complex V subunits are nuclear encoded and so far, were not found in association with recognized Mendelian disorders. ATP5PO is a candidate gene for complex V mitochondrial disease. It encodes the oligomycin sensitivity-conferring protein (OSCP), an essential component of the "stalk" region that links the F1 and F0 domains of the ATP synthase complex. We report a 4-month-old girl, born at 35 weeks' gestation to a consanguineous couple via cesarean section due to fetal growth restriction and antenatal echocardiographic findings of moderate biventricular hypertrophy. At birth, she required intubation, ventilation, and surfactant therapy. The patient experienced intermittent hyperlactatemia, apneic spells, encephalopathy, axial hypotonia, and abnormal neonatal reflexes. She passed away at 4 months of age, and whole-exome sequencing revealed a homozygous splice variant (c.87 + 3A > G; p?) in ATP5PO. This gene was reported as a candidate gene, where additional evidence is needed to establish whether there is a relationship between this gene variant and human disease. So far and to our best knowledge, only four cases with a pathogenic variant in this gene have been reported. Mitochondrial respiratory chain analysis performed on fibroblasts revealed reduced ATPase enzyme activity with approximately 35% of the mean enzyme activity observed in the control reference range, with a decreased enzyme activity ratio relative to citrate synthase. These results suggest that isolated complex V enzyme deficiency is associated with the homozygous VUS identified in the ATP5PO gene in this patient and provide further functional support that ATP5PO is involved in complex V assembly and function.