Abstract
Autosomal dominant progressive external ophthalmoplegia is a rare human disease that shows a Mendelian inheritance pattern, but is characterized by large-scale mitochondrial DNA (mtDNA) deletions. We have identified two heterozygous missense mutations in the nuclear gene encoding the heart/skeletal muscle isoform of the adenine nucleotide translocator (ANT1) in five families and one sporadic patient. The familial mutation substitutes a proline for a highly conserved alanine at position 114 in the ANT1 protein. The analogous mutation in yeast caused a respiratory defect. These results indicate that ANT has a role in mtDNA maintenance and that a mitochondrial disease can be caused by a dominant mechanism.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Amino Acid Substitution
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Animals
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DNA, Mitochondrial / genetics*
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DNA, Mitochondrial / metabolism*
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Female
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Founder Effect
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Genes, Dominant
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Humans
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Isoenzymes / chemistry
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Italy
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Male
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Mitochondrial ADP, ATP Translocases / chemistry
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Mitochondrial ADP, ATP Translocases / genetics*
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Mitochondrial ADP, ATP Translocases / metabolism*
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Molecular Sequence Data
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Mutation, Missense
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Ophthalmoplegia, Chronic Progressive External / enzymology
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Ophthalmoplegia, Chronic Progressive External / genetics*
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Oxygen Consumption
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Pedigree
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Point Mutation
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Saccharomyces cerevisiae / enzymology
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism
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Sequence Deletion
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Transformation, Genetic
Substances
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DNA, Mitochondrial
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Isoenzymes
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Mitochondrial ADP, ATP Translocases