{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:19:00Z","timestamp":1790680740843,"version":"4.1.0"},"reference-count":25,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T00:00:00Z","timestamp":1657497600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54NS078059"],"award-info":[{"award-number":["U54NS078059"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K08DK113250"],"award-info":[{"award-number":["K08DK113250"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006086","name":"Office of Strategic Coordination","doi-asserted-by":"publisher","award":["U01HG007690"],"award-info":[{"award-number":["U01HG007690"]}],"id":[{"id":"10.13039\/100006086","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2022,9]]},"abstract":"Abstract<\/jats:title>\n \n 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\n ATP5PO<\/jats:italic>\n , 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\u2010systemic 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\u2010length 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\n ATP5PO<\/jats:italic>\n cDNA without exon 2 (h\n ATP5PO<\/jats:italic>\n \u2010\u2206ex2) in yeast cells deleted for\n yATP5<\/jats:italic>\n (\n ATP5PO<\/jats:italic>\n homolog) was unable to rescue growth on media which requires oxidative phosphorylation when compared to the wild type construct (h\n ATP5PO<\/jats:italic>\n \u2010WT), indicating that exon 2 deletion leads to a non\u2010functional protein. Collectively, our findings support the pathogenicity of the\n ATP5PO<\/jats:italic>\n 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\n ATP5PO<\/jats:italic>\n variants, add to the evidence that rare biallelic variants in\n ATP5PO<\/jats:italic>\n result in defective complex V assembly, function and are associated with Leigh syndrome.\n <\/jats:p>","DOI":"10.1002\/jimd.12526","type":"journal-article","created":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T07:59:49Z","timestamp":1653638389000},"page":"996-1012","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["A homozygous splice variant in\n \n ATP5PO<\/i>\n <\/scp>\n , disrupts mitochondrial complex V function and causes Leigh syndrome in two unrelated families"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2834-0843","authenticated-orcid":false,"given":"Mythily","family":"Ganapathi","sequence":"first","affiliation":[{"name":"Department of Pathology & Cell Biology Columbia 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