Heterogeneous tissue distribution of a mitochondrial DNA polymorphism in heteroplasmic subjects without mitochondrial disorders

• Published in: Journal of medical genetics Vol. 38; no. 5; pp. 312 - 317
• Main Authors: Kirches, Elmar, Michael, Matthias, Warich-Kirches, Michaela, Schneider, Thomas, Weis, Serge, Krause, Guido, Mawrin, Christian, Dietzmann, Knut
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.05.2001; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Abnormalities; Adolescent; Adult; Aged; Aged, 80 and over; Base Sequence; Biological and medical sciences; Brain; Brain - cytology; Brain - metabolism; Child; Deoxycytidine - genetics; DNA Mutational Analysis; DNA, Mitochondrial - genetics; Errors of metabolism; Female; Gene mutations; Genomes; Genotype; Health aspects; heteroplasmy; Humans; HVR2; Lasers; Male; Medical sciences; Metabolic diseases; Middle Aged; Miscellaneous hereditary metabolic disorders; Mitochondrial DNA; Mitochondrial Myopathies - genetics; Models, Genetic; mtDNA; Mutation; Mutation - genetics; Oocytes - cytology; Oocytes - metabolism; Organ Specificity; Original; Patients; Phenotype; Physiological aspects; Polymerase Chain Reaction; polymorphism; Polymorphism, Genetic - genetics; Polymorphism, Restriction Fragment Length; Regulatory Sequences, Nucleic Acid - genetics; Selection, Genetic; Transfer RNA; United Kingdom; Germany; Human; Pathogenesis; Metabolic diseases; Exploration; Hypervariable region; Mitochondrial DNA; Enzymopathy; Mitochondrial disorder; Genetic disease; Segregation analysis; Tissue; Heteroplasmy; Distribution; Comparative study; Brain (vertebrata); Polymorphism
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.38.5.312

CONTEXT Several maternally inherited point mutations of the mitochondrial genome cause mitochondrial disorders, but the correlation between genotype and phenotype remains obscure in many cases. The same mutation may cause various diseases, probably because of a different tissue distribution. OBJECTIVE To assess the role of random somatic segregation in generating interperson differences by analysis of an apparently neutral polymorphism. DESIGN Screening of 81 brain samples from subjects without mitochondrial disorders and selection of five necropsy cases showing a high level of heteroplasmy for the polymorphism. MAIN OUTCOME MEASURES A proportion of various distinct genotypes in the mtDNA pool of the tissues, identified by fluorescent PCR products, representing a short polycytosine tract of variable length in the mitochondrial displacement loop. RESULTS Differences were found between organs or groups of organs within subjects, pointing towards somatic segregation of mtDNA. In addition, marked differences of this organ distribution occurred between subjects, which cannot be explained by tissue specific selection. CONCLUSIONS The observed interperson differences can be explained by somatic segregation, which occurs randomly at various developmental stages. Besides tissue specific selection, this process might participate in the distribution of pathogenic mtDNA mutations.