{Reference Type}: Journal Article
{Title}: A homozygous splice variant in ATP5PO, disrupts mitochondrial complex V function and causes Leigh syndrome in two unrelated families.
{Author}: Ganapathi M;Friocourt G;Gueguen N;Friederich MW;Le Gac G;Okur V;Loaëc N;Ludwig T;Ka C;Tanji K;Marcorelles P;Theodorou E;Lignelli-Dipple A;Voisset C;Walker MA;Briere LC;Bourhis A;Blondel M;LeDuc C;Hagen J;Cooper C;Muraresku C;Ferec C;Garenne A;Lelez-Soquet S;Rogers CA;Shen Y;Strode DK;Bizargity P;Iglesias A;Goldstein A;High FA;Network UD;Sweetser DA;Ganetzky R;Van Hove JLK;Procaccio V;Le Marechal C;Chung WK;
{Journal}: J Inherit Metab Dis
{Volume}: 45
{Issue}: 5
{Year}: 09 2022
{Factor}: 4.75
{DOI}: 10.1002/jimd.12526
{Abstract}: Mitochondrial complex V plays an important role in oxidative phosphorylation by catalyzing the generation of ATP. Most complex V subunits are nuclear encoded and not yet associated with recognized Mendelian disorders. Using exome sequencing, we identified a rare homozygous splice variant (c.87+3A>G) in ATP5PO, the complex V subunit which encodes the oligomycin sensitivity conferring protein, in three individuals from two unrelated families, with clinical suspicion of a mitochondrial disorder. These individuals had a similar, severe infantile and often lethal multi-systemic disorder that included hypotonia, developmental delay, hypertrophic cardiomyopathy, progressive epileptic encephalopathy, progressive cerebral atrophy, and white matter abnormalities on brain MRI consistent with Leigh syndrome. cDNA studies showed a predominant shortened transcript with skipping of exon 2 and low levels of the normal full-length transcript. Fibroblasts from the affected individuals demonstrated decreased ATP5PO protein, defective assembly of complex V with markedly reduced amounts of peripheral stalk proteins, and complex V hydrolytic activity. Further, expression of human ATP5PO cDNA without exon 2 (hATP5PO-∆ex2) in yeast cells deleted for yATP5 (ATP5PO homolog) was unable to rescue growth on media which requires oxidative phosphorylation when compared to the wild type construct (hATP5PO-WT), indicating that exon 2 deletion leads to a non-functional protein. Collectively, our findings support the pathogenicity of the ATP5PO c.87+3A>G variant, which significantly reduces but does not eliminate complex V activity. These data along with the recent report of an affected individual with ATP5PO variants, add to the evidence that rare biallelic variants in ATP5PO result in defective complex V assembly, function and are associated with Leigh syndrome.