title: Pathogenesis of the deafness-associated A1555G mitochondrial DNA mutation.
abstract: The pathogenic mechanisms of the A1555G mitochondrial DNA mutation in the 12S rRNA gene, associated with maternally inherited sensorineural deafness, are largely unknown. Previous studies have suggested an involvement of nuclear factor(s). To address this issue cybrids were generated by fusing osteosarcoma cells devoid of mtDNA with enucleated fibroblasts from two genetically unrelated patients. Furthermore, to determine the contribution, if any, of the mitochondrial and nuclear genomes, separately or in combination, in the expression of the disease phenotype, transmitochondrial fibroblasts were constructed using control and patient's fibroblasts as nuclear donors and homoplasmic mutant or wild-type cybrids as mitochondrial donors. Detailed analysis of mutant and wild-type cybrids from both patients and transmitochondrial fibroblast clones did not reveal any respiratory chain dysfunction suggesting that, if nuclear factors do indeed act as modifier agents, they may be tissue-specific. However, in the presence of high concentrations of neomycin or paromomycin, but not of streptomycin, mutant cells exhibit a decrease in the growth rate, when compared to wild-type cells. The decrease did not correlate with the rate of synthesis or stability of mitochondrial DNA-encoded subunits or respiratory chain activity. Further studies are required to determine the underlying biochemical defect.
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, Room 5-431, 630 West 168th Street, Columbia, NY 10032, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Giordano
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallotti
authors.forename: Winsome F
authors.initials: WF
authors.lastname: Walker
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Checcarelli
authors.forename: Olimpia
authors.initials: O
authors.lastname: Musumeci
authors.forename: Filippo
authors.initials: F
authors.lastname: Santorelli
authors.forename: Giulia
authors.initials: G
authors.lastname: d'Amati
authors.forename: Eric A
authors.initials: EA
authors.lastname: Schon
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiMauro
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.forename: Mercy M
authors.initials: MM
authors.lastname: Davidson
mesh_terms: D000328:Adult; D002455:Cell Division; D002478:Cells, Cultured; D002999:Clone Cells; D004272:DNA, Mitochondrial / Q000235:genetics*; D003638:Deafness / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008875:Middle Aged; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D012335:RNA, Ribosomal / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S