Evidence and age-related distribution of mtDNA D-loop point mutations in skeletal muscle from healthy subjects and mitochondrial patients

• Published in: Journal of the neurological sciences Vol. 202; no. 1-2; pp. 85 - 91
• Main Authors: Del Bo, Roberto, Bordoni, Andreina, Boneschi, Filippo Martinelli, Crimi, Marco, Sciacco, Monica, Bresolin, Nereo, Scarlato, Guglielmo, Comi, Giacomo Pietro
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 15.10.2002; Elsevier Science
• Subjects: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Ageing; Biological and medical sciences; Biopsy; Blotting, Southern; Child; Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes; DNA Mutational Analysis; DNA, Mitochondrial - genetics; Gene Deletion; Humans; Medical sciences; Middle Aged; Mitochondria, Muscle - physiology; Mitochondrial DNA; Mitochondrial encephalomyopathies; Mitochondrial Encephalomyopathies - genetics; Multiple deletions; Muscle, Skeletal - physiology; Muscle, Skeletal - ultrastructure; Nervous system (semeiology, syndromes); Neurology; Peptides, Cyclic - genetics; Point Mutation; Polymerase Chain Reaction; Skeletal muscle; Somatic point mutations; Mitochondrial DNA; Multiple deletions; Mitochondrial encephalomyopathies; Somatic point mutations; Ageing; Skeletal muscle; Chromosomal aberration; Human; Nervous system diseases; Multiple; Exploration; Striated muscle; Cerebral disorder; Central nervous system disease; Mitochondrial encephalopathy; Point mutation; Deletion; Abnormal chromosome; Elderly
• ISSN: 0022-510X; 1878-5883
• DOI: 10.1016/S0022-510X(02)00247-2

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.