Biallelic Loss-Of-Function Variant in ATP5ME Is Associated With Severe and Early Onset Oxidative Phosphorylation...

ATP synthase (complex V) catalyzes ATP synthesis and is composed of the F₁ catalytic sector and the F₀ proton-conducting sector. The e subunit of the F₀ sector, encoded by ATP5ME, is essential for complex V dimerization and cristae organization; however, genetic variants in ATP5ME have not yet been implicated in human disease. We ascertained a 4-year-old male, born of a consanguineous marriage, who presented with neuroregression, feeding difficulty, spasticity, encephalopathy, bilateral sensorineural hearing loss and optic atrophy. Exome sequencing identified a biallelic 62 bp deletion, c.-48_14del in ATP5ME (NM_007100.4; NC_000004.12: g.674234_674295del), spanning the upstream sequence, the 5' untranslated region, and part of exon 1. Patient-derived fibroblasts exhibited markedly decreased ATP5ME transcript and protein levels, accompanied by a reduction in the expression of complex I, IV, and V subunits. In vitro assays demonstrated reduced activities of complexes I, IV, and V, impaired mitochondrial respiration, reduced reactive oxygen species levels, decreased mitochondrial membrane potential, and reduced ATP levels. Additionally, atp5me knockout zebrafish demonstrated a severe developmental phenotype characterized by craniofacial defects, reduced locomotion, and decreased ATP levels. This was accompanied by reduced protein levels of complex II and IV subunits, mild decrease in mtDNA, and upregulation of genes associated with glycolysis and oxidative stress. All observed phenotypes were rescued by human ATP5ME mRNA complementation, thereby validating the pathogenicity of ATP5ME deficiency in vivo.