title: A novel mitochondrial DNA m.7507A>G mutation is only pathogenic at high levels of heteroplasmy.
abstract: We present a Dutch family with a novel disease-causing mutation in the mitochondrial tRNA(Ser(UCN)) gene, m.7507A>G. The index patient died during the neonatal period due to cardio-respiratory failure and fatal lactic acidosis. A second patient, his cousin, has severe hearing loss necessitating cochlear implants and progressive exercise intolerance. Laboratory investigations of both patients revealed combined deficiencies of the enzyme complexes of the mitochondrial respiratory chain in several tissues. Reduced levels of fully assembled complexes I and IV in fibroblasts by BN-PAGE associated with (near) homoplasmic levels of the m.7507A>G mutation in several tissues and a severe reduction in the steady-state level of mt-tRNA(Ser(UCN)) in fibroblasts were observed. The novel mitochondrial DNA mutation was shown to segregate with disease; several healthy maternal family members showed high heteroplasmy levels (up to 76 ± 4% in blood and 68 ± 4% in fibroblasts) which did not lead to any alterations in the activities of the enzyme complexes of the respiratory chain in fibroblasts or clinical signs and symptoms. We hereby conclude that the m.7507A>G mutation causes a heterogeneous clinical phenotype and is only pathogenic at very high levels of mtDNA heteroplasmy.
authors.affiliation: Nijmegen Centre for Mitochondrial Disorders (NCMD), Amalia Children's Hospital, Nijmegen, The Netherlands; Department of Biology, Darmstadt University of Technology, Darmstadt, Germany.
authors.forename: Beverly Jo
authors.initials: BJ
authors.lastname: McCann
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Helen A L
authors.initials: HA
authors.lastname: Tuppen
authors.affiliation: Department of Pathology, Radboudumc, Nijmegen, The Netherlands; Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Benno
authors.initials: B
authors.lastname: Küsters
authors.affiliation: Department of Pathology, Antwerp University Hospital, Antwerp, Belgium; University of Antwerp, Antwerp, Belgium.
authors.forename: Martin
authors.initials: M
authors.lastname: Lammens
authors.affiliation: Nijmegen Centre for Mitochondrial Disorders (NCMD), Amalia Children's Hospital, Nijmegen, The Netherlands.
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Nijmegen Centre for Mitochondrial Disorders (NCMD), Amalia Children's Hospital, Nijmegen, The Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Nijmegen Centre for Mitochondrial Disorders (NCMD), Amalia Children's Hospital, Nijmegen, The Netherlands. Electronic address: Saskia.Wortmann-Hagemann@radboudumc.nl.
authors.forename: Saskia B
authors.initials: SB
authors.lastname: Wortmann
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000328:Adult; D002478:Cells, Cultured; D002675:Child, Preschool; D004272:DNA, Mitochondrial; D005190:Family; D017809:Fatal Outcome; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006333:Heart Failure / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D012362:RNA, Transfer, Ser / Q000235:genetics*; D012131:Respiratory Insufficiency / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
chemical_list: D004272:DNA, Mitochondrial; D012362:RNA, Transfer, Ser
keywords: Hearing loss; Heteroplasmy; Mitochondrial tRNA; OXPHOS; Threshold effect