{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T03:47:40Z","timestamp":1772682460522,"version":"3.50.1"},"reference-count":28,"publisher":"BMJ","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[2008,2]]},"abstract":"<jats:sec>\n                  <jats:title>Background:<\/jats:title>\n                  <jats:p>MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) is one of the more common mitochondrial encephalomyopathies. About 80% of MELAS cases are caused by transition 3243A\u2192G in the mitochondrial tRNA<jats:sup>Leu(UUR)<\/jats:sup> gene (<jats:italic>MT-TL1<\/jats:italic>). Other mutations in <jats:italic>MT-TL1<\/jats:italic>, other mitochondrial tRNA genes and mitochondrial-encoded subunits of respiratory complex\u00a0I account for the remainder of cases.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective:<\/jats:title>\n                  <jats:p>To characterise the molecular basis of a MELAS case without a mutation in any recognised MELAS target gene.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results and methods:<\/jats:title>\n                  <jats:p>Deletion of a single nucleotide (7630delT) within <jats:italic>MT-CO2<\/jats:italic>, the gene of subunit II of cytochrome c oxidase (COX), was identified by mitochondrial DNA (mtDNA) sequencing. The deletion-induced frameshift results in a stop codon close to the 5\u2032 end of the reading frame. The lack of subunit II (COII) precludes the assembly of COX and leads to the degradation of unassembled subunits, even those not directly affected by the mutation. Despite mitochondrial proliferation and transcriptional upregulation of nuclear and mtDNA-encoded COX genes (including <jats:italic>MT-CO2<\/jats:italic>), a severe COX deficiency was found with all investigations of the muscle biopsy (histochemistry, biochemistry, immunoblotting).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions:<\/jats:title>\n                  <jats:p>The 7630delT mutation in <jats:italic>MT-CO2<\/jats:italic> leads to a lack of COII with subsequent misassembly and degradation of respiratory complex IV despite transcriptional upregulation of its subunits. The causal association of the resulting isolated COX deficiency with MELAS is at odds with current concepts of the biochemical deficits underlying this common mitochondrial disease, and indicates that the genetic and pathobiochemical heterogeneity of MELAS is greater than previously appreciated.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg.2007.052076","type":"journal-article","created":{"date-parts":[[2008,2,1]],"date-time":"2008-02-01T13:35:30Z","timestamp":1201872930000},"page":"117-121","source":"Crossref","is-referenced-by-count":28,"title":["Isolated cytochrome c oxidase deficiency as a cause of MELAS"],"prefix":"10.1136","volume":"45","author":[{"given":"W","family":"Rossmanith","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Freilinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Roka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T","family":"Raffelsberger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K","family":"Moser-Thier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D","family":"Prayer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G","family":"Bernert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R E","family":"Bittner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2008,2,1]]},"reference":[{"key":"2025101714154466000_45.2.117.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0070-2153(06)77005-3"},{"key":"2025101714154466000_45.2.117.2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410160409"},{"key":"2025101714154466000_45.2.117.3","doi-asserted-by":"publisher","DOI":"10.1177\/088307389400900102"},{"key":"2025101714154466000_45.2.117.4","doi-asserted-by":"publisher","DOI":"10.1586\/14737159.4.5.631"},{"key":"2025101714154466000_45.2.117.5","doi-asserted-by":"publisher","DOI":"10.2165\/00023210-200620060-00002"},{"key":"2025101714154466000_45.2.117.6","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.020537"},{"key":"2025101714154466000_45.2.117.7","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10435"},{"key":"2025101714154466000_45.2.117.8","doi-asserted-by":"publisher","DOI":"10.1055\/s-2002-33679"},{"key":"2025101714154466000_45.2.117.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2003.12.004"},{"key":"2025101714154466000_45.2.117.10","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10753"},{"key":"2025101714154466000_45.2.117.11","unstructured":"Sambrook J Russell DW . 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