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

Context-Several maternally inherited point mutations of the mitochondrial g enome cause mitochondrial disorders, but the correlation between genotype a nd phenotype remains obscure in many cases. The same mutation may cause var ious diseases, probably because of a different tissue distribution. Objective-To assess the role of random somatic segregation in generating in terperson differences by analysis of an apparently neutral polymorphism. Design-Screening of 81 brain samples from subjects without mitochondrial di sorders and selection of five necropsy cases showing a high level of hetero plasmy for the polymorphism. Main outcome measures-A proportion of various distinct genotypes in the mtD NA pool of the tissues, identified by fluorescent PCR products, representin g a short polycytosine tract of variable length in the mitochondrial displa cement loop. Results-Differences were found between organs or groups of organs within su bjects, pointing towards somatic segregation of mtDNA. In addition, marked differences of this organ distribution occurred between subjects, which can not be explained by tissue specific selection. Conclusions-The observed interperson differences can be explained by somati c segregation, which occurs randomly at various developmental stages. Besid es tissue specific selection, this process might participate in the distrib ution of pathogenic mtDNA mutations.