%0 Journal Article
%T A homozygous splice variant in ATP5PO, disrupts mitochondrial complex V function and causes Leigh syndrome in two unrelated families.
%A Ganapathi M
%A Friocourt G
%A Gueguen N
%A Friederich MW
%A Le Gac G
%A Okur V
%A Loaëc N
%A Ludwig T
%A Ka C
%A Tanji K
%A Marcorelles P
%A Theodorou E
%A Lignelli-Dipple A
%A Voisset C
%A Walker MA
%A Briere LC
%A Bourhis A
%A Blondel M
%A LeDuc C
%A Hagen J
%A Cooper C
%A Muraresku C
%A Ferec C
%A Garenne A
%A Lelez-Soquet S
%A Rogers CA
%A Shen Y
%A Strode DK
%A Bizargity P
%A Iglesias A
%A Goldstein A
%A High FA
%A Network UD
%A Sweetser DA
%A Ganetzky R
%A Van Hove JLK
%A Procaccio V
%A Le Marechal C
%A Chung WK
%J J Inherit Metab Dis
%V 45
%N 5
%D 09 2022
%M 35621276
%F 4.75
%R 10.1002/jimd.12526
%X 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.