title: Nucleus-driven multiple large-scale deletions of the human mitochondrial genome: a new autosomal dominant disease.
abstract: We studied several affected and one nonaffected individuals belonging to three unrelated pedigrees. The pathological trait was an autosomal dominant mitochondrial myopathy due to large-scale multiple deletions of the mitochondrial genome. Clinically, symptomatic patients had progressive external ophthalmoplegia, muscle weakness and wasting, sensorineural hypoacusia, and, in some cases, vestibular areflexia and tremor. The muscle biopsies of all patients examined showed ragged-red fibers, neurogenic changes, and a partially decreased histochemical reaction to cytochrome c oxidase. Multiple mtDNA heteroplasmy was detected in the patients by both Southern blot analysis and PCR amplification, whereas the unaffected individual had the normal homoplasmic hybridization pattern. These findings confirm and add further details to the existence of a new human disease--defined clinically as a mitochondrial myopathy, genetically as a Mendelian autosomal dominant trait, and molecularly by the accumulation of multiple, large-scale deletions of the mitochondrial genome--that is due to impaired nuclear control during mtDNA replication.
authors.affiliation: National Neurological Institute, Carlo Besta, Department of Biochemistry and Genetics, State University School of Medicine, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Zeviani
authors.forename: N
authors.initials: N
authors.lastname: Bresolin
authors.forename: C
authors.initials: C
authors.lastname: Gellera
authors.forename: A
authors.initials: A
authors.lastname: Bordoni
authors.forename: M
authors.initials: M
authors.lastname: Pannacci
authors.forename: P
authors.initials: P
authors.lastname: Amati
authors.forename: M
authors.initials: M
authors.lastname: Moggio
authors.forename: S
authors.initials: S
authors.lastname: Servidei
authors.forename: G
authors.initials: G
authors.lastname: Scarlato
authors.forename: S
authors.initials: S
authors.lastname: DiDonato
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D015139:Blotting, Southern; D002467:Cell Nucleus / Q000378:metabolism*; D002872:Chromosome Deletion; D002877:Chromosomes, Human; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism*; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009886:Ophthalmoplegia / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D004272:DNA, Mitochondrial