A homozygous splice variant in ATP5PO, disrupts mitochondrial complex V function and causes Leigh syndrome in two unrelated families.
Mythily GanapathiGaelle FriocourtNaig GueguenMarisa W FriederichGerald Le GacVolkan OkurNadège LoaëcThomas LudwigChandran KaKurenai TanjiPascale MarcorellesEvangelos TheodorouAngela Lignelli-DippleCécile VoissetMelissa A WalkerLauren C BriereAmélie BourhisMarc BlondelCharles A LeDucJacob HagenCathleen CooperColleen MurareskuClaude FerecArmelle GarenneServane Lelez-SoquetCassandra A RogersYufeng ShenDana K StrodePeyman BizargityAlejandro IglesiasAmy GoldsteinFrances A HighUndiagnosed Diseases NetworkDavid A SweetserRebecca D GanetzkyJohan L K Van HoveVincent ProcaccioCedric Le MarechalWendy K ChungPublished in: Journal of inherited metabolic disease (2022)
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.
Keyphrases
- white matter
- visible light
- multiple sclerosis
- oxidative stress
- gene expression
- poor prognosis
- early onset
- machine learning
- small molecule
- left ventricular
- rna seq
- long non coding rna
- magnetic resonance
- cell cycle arrest
- artificial intelligence
- subarachnoid hemorrhage
- deep learning
- resting state
- functional connectivity
- cerebral ischemia
- data analysis
- staphylococcus aureus
- pi k akt
- drug induced