title: Mitochondrial DNA mutations in Leigh syndrome and their phylogenetic implications.
abstract: Of 100 patients with the clinical diagnosis of Leigh syndrome, 21 were found to have specific enzyme defects: 15 involving cytochrome c oxidase (COX); 4, pyruvate dehydrogenase complex (PDHC); one, complex I (reduced nicotinamide adenine dinucleotide [NADH]-coenzyme Q reductase) and one, complex II (succinate-ubiquinone reductase) deficiencies. In addition to the most common form of COX deficiency, mtDNA mutations in the adenosine triphosphatase (ATPase) 6 coding region were also commonly seen. Eighteen patients (18%) had mtDNA mutations at nucleotide position (np) 8993 or 9176. The mutated DNAs were present in a heteroplasmic state, comprising more than 90% of the DNA in muscle and/or blood samples from all patients. Patients with the T-to-G mutation at np 8993 usually had early onset of the disease with rapid progression, showing the typical clinical features of Leigh syndrome. On the other hand, those with the T-to-C 8993 mutation showed a milder and more chronic course. Patients with the mutation at np 9176 showed variable courses. Phylogenetic analysis of mtDNA D-loop sequences for the patients with the ATPase 6 mutations and normal Japanese subjects revealed that a T-to-G/C mutation at np 8993 and a T-to-C mutation at np 9176 occurred many times independently in the Japanese population.
authors.affiliation: Department of Ultrastructural Research, National Institute of Neuroscience, NCNP, Tokyo, Japan. makino@ncnp.go.jp
authors.forename: M
authors.initials: M
authors.lastname: Makino
authors.forename: S
authors.initials: S
authors.lastname: Horai
authors.forename: Y
authors.initials: Y
authors.lastname: Goto
authors.forename: I
authors.initials: I
authors.lastname: Nonaka
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D010802:Phylogeny; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D011768:Pyruvate Dehydrogenase Complex; D003576:Electron Transport Complex IV; D000251:Adenosine Triphosphatases