Journal
JOURNAL OF INHERITED METABOLIC DISEASE
Volume 45, Issue 5, Pages 996-1012Publisher
WILEY
DOI: 10.1002/jimd.12526
Keywords
ATP synthase; ATP5PO; complex V; OSCP oligomycin sensitivity conferring protein; mitochondria; splice variant; mitochondrial disease; Leigh syndrome; hypertrophic cardiomyopathy; seizure; yeast ATP5
Funding
- National Institutes of Health [U54NS078059, K08DK113250]
- Hill Family
- Office of Strategic Coordination/Office of the NIH [U01HG007690]
Ask authors/readers for more resources
Mitochondrial complex V is important for oxidative phosphorylation and a rare variant in ATP5PO gene is associated with a severe multi-systemic disorder consistent with Leigh syndrome.
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- increment 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available