Mitochondrial DNA mutations in Leigh syndrome and their phylogenetic implications |
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Authors: | M Makino S Horai Y Goto I Nonaka |
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Institution: | (1) Department of Ultrastructural Research, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan Tel. +81-42-346-1719; Fax +81-42-346-1749 e-mail: makino@ncnp.go.jp, JP;(2) Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, NCNP, Tokyo, Japan, JP;(3) Department of Biosystems Science, The Graduate University for Advanced Studies, Kanagawa, Japan, JP |
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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.
Received: September 21, 1999 / Accepted: November 24, 1999 |
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Keywords: | Leigh Mitochondria ATPase Phylogeny |
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