title: Evidence and age-related distribution of mtDNA D-loop point mutations in skeletal muscle from healthy subjects and mitochondrial patients.
abstract: The progressive accumulation of mitochondrial DNA (mtDNA) alterations, ranging from single mutations to large-scale deletions, in both the normal ageing process and pathological conditions is a relevant phenomenon in terms of frequency and heteroplasmic degree. Recently, two point mutations (A189G and T408A) within the Displacement loop (D-loop) region, the control region for mtDNA replication, were shown to occur in skeletal muscles from aged individuals. We evaluated the presence and the heteroplasmy levels of these two mutations in muscle biopsies from 91 unrelated individuals of different ages (21 healthy subjects and 70 patients affected by mitochondrial encephalomyopathies). Overall, both mutations significantly accumulate with age. However, a different relationship was discovered among the different subgroups of patients: a higher number of A189G positive subjects younger than 53 years was detected in the subgroup of multiple-deleted patients; furthermore, a trend towards an increased risk for the mutations was evidenced among patients carrying multiple deletions when compared to healthy controls. These findings support the idea that a common biological mechanism determines the accumulation of somatic point mutations in the D-loop region, both in healthy subjects and in mitochondrial myopathy patients. At the same time, it appears that disorders caused by mutations of nuclear genes controlling mtDNA replication (the "mtDNA multiple deletions" syndromes) present a temporal advantage to mutate in the D-loop region. This observation may be relevant to the definition of the molecular pathogenesis of these latter syndromes.
authors.affiliation: Department of Neurological Sciences, Centro Dino Ferrari, Padiglione Ponti, University of Milan, IRCCS Ospedale Maggiore Policlinico, 20122, Via F Sforza, 35, 20122 Milan, Italy. gpcomi@mailserver.unimi.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Del Bo
authors.forename: Andreina
authors.initials: A
authors.lastname: Bordoni
authors.forename: Filippo
authors.initials: F
authors.lastname: Martinelli Boneschi
authors.forename: Marco
authors.initials: M
authors.lastname: Crimi
authors.forename: Monica
authors.initials: M
authors.lastname: Sciacco
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Scarlato
authors.forename: Giacomo Pietri
authors.initials: GP
authors.lastname: Comi
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D015139:Blotting, Southern; D002648:Child; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000502:physiology*; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics*; D018482:Muscle, Skeletal / Q000502:physiology* / Q000648:ultrastructure; D010456:Peptides, Cyclic / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction
chemical_list: D004272:DNA, Mitochondrial; D010456:Peptides, Cyclic; C078763:D-loop peptide, synthetic