Novel Twinkle (PEO1) gene mutations in mendelian progressive external ophthalmoplegia
Multiple deletions of mitochondrial DNA (mtDNA) are associated with different mitochondrial disorders inherited as autosomal dominant and recessive traits. Causative mutations have been found in five genes, mainly involved in mtDNA replication and stability. They include POLG1 , the gene encoding th...
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Veröffentlicht in: | Journal of neurology 2008-09, Vol.255 (9), p.1384-1391 |
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Sprache: | eng |
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Zusammenfassung: | Multiple deletions of mitochondrial DNA (mtDNA) are associated with different mitochondrial disorders inherited as autosomal dominant and recessive traits. Causative mutations have been found in five genes, mainly involved in mtDNA replication and stability. They include
POLG1
, the gene encoding the catalytic subunit of mtDNA polymerase (polγ),
POLG2
encoding its accessory subunit,
ANT1
coding the adenine nucleotide translocator and
PEO1
which codes for Twinkle, the mitochondrial helicase. Finally
OPA1
missense mutations are involved in phenotypes presenting optic atrophy as a major feature.
To define the relative contribution of
POLG1, POLG2, ANT1
and
PEO1
genes to the mtDNA multiple deletion syndromes, we analysed them in a cohort of 67 probands showing accumulation of multiple mtDNA deletions in muscle. The patients were predominantly affected with a mitochondrial myopathy with or without progressive external ophthalmoplegia (PEO). Genetic analysis revealed that 1)
PEO1
has a major role in determining familial PEO, since it accounts for 26.8 % of familial cases, followed by
ANT1
(14.6 %) and
POLG1
(9.8 %); 2) no mutations in any of the known genes were found in 53.7 % of probands of this series. Six novel missense mutations contributing to the mutational load of
PEO1
gene (p.R334P, p.W315S, p. S426N, p.W474S, p.F478I, p.E479K) were associated with an adult onset PEO phenotype. |
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ISSN: | 0340-5354 1432-1459 |
DOI: | 10.1007/s00415-008-0926-3 |