title: Increased incidence of mitochondrial cytochrome c-oxidase gene mutations in patients with myelodysplastic syndromes.
abstract: Mitochondria (mt) play an important role in both apoptosis and haem synthesis. The present study was conducted to determine DNA mutations in mitochondrial encoded cytochrome c-oxidase I and II genes. Bone marrow (BM) biopsy and aspirate, peripheral blood (PB) and buccal smear samples were collected from 20 myelodysplastic syndrome (MDS) patients and 10 age-matched controls. Cytochrome c-oxidase I (CO I) and II (CO II) genes were amplified using polymerase chain reaction and sequenced. CO I mutations were found in 13/20 MDS patients and the CO II gene in 2/10 normal and 12/20 MDS samples, irrespective of MDS subtype. Mutations were substitutional, deletional and insertional. CO I mutations were most common at nucleotide positions 7264 (25%) and 7289 (15%), and CO II mutations were most common at nucleotide positions 7595 (40%) and 7594 (30%), suggesting the presence of potential 'hot-spots'. Mutations were not found in buccal smears of MDS patients and were significantly higher in MDS samples compared with age-matched controls in all cell fractions (P < 0.05), with bone marrow high-density fraction (BMHDF) showing a higher mutation rate than other fractions (P < 0.05). MDS marrows showed higher levels of apoptosis than normal controls (P < 0.05), and apoptosis in BMHDF was directly related to cytochrome c-oxidase I gene mutations (P < 0.05). Electron microscopy revealed apoptosis affecting all haematopoietic lineages with highly abnormal, iron-laden mitochondria. These results suggest a role for mt-DNA mutations in the excessive apoptosis and resulting cytopenias of MDS patients.
authors.affiliation: Rush Cancer Institute, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612-3515, USA.
authors.forename: Poluru L
authors.initials: PL
authors.lastname: Reddy
authors.forename: Vilasini T
authors.initials: VT
authors.lastname: Shetty
authors.forename: Diya
authors.initials: D
authors.lastname: Dutt
authors.forename: Aaron
authors.initials: A
authors.lastname: York
authors.forename: Saleem
authors.initials: S
authors.lastname: Dar
authors.forename: Suneel D
authors.initials: SD
authors.lastname: Mundle
authors.forename: Krishnan
authors.initials: K
authors.lastname: Allampallam
authors.forename: Sairah
authors.initials: S
authors.lastname: Alvi
authors.forename: Naomi
authors.initials: N
authors.lastname: Galili
authors.forename: Gurveen Sethi
authors.initials: GS
authors.lastname: Saberwal
authors.forename: Shalini
authors.initials: S
authors.lastname: Anthwal
authors.forename: Malihi
authors.initials: M
authors.lastname: Shaikh
authors.forename: Samia
authors.initials: S
authors.lastname: Suleman
authors.forename: Shaista Y
authors.initials: SY
authors.lastname: Kamal
authors.forename: Azra
authors.initials: A
authors.lastname: Raza
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000201:enzymology / Q000648:ultrastructure; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics*; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology* / Q000648:ultrastructure; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV