title: A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy.
abstract: OBJECTIVE
  The purpose of this study was to understand the clinical and molecular features of familial hypertrophic cardiomyopathy (HCM) in which a mitochondrial abnormality was strongly suspected.
  
  
  BACKGROUND
  Defects of the mitochondrial genome are responsible for a heterogeneous group of clinical disorders, including cardiomyopathy. The majority of pathogenic mutations are heteroplasmic, with mutated and wild-type mitochondrial deoxyribonucleic acid (mtDNA) coexisting within the same cell. Homoplasmic mutations (present in every copy of the genome within the cell) present a difficult challenge in terms of diagnosis and assigning pathogenicity, as human mtDNA is highly polymorphic.
  
  
  METHODS
  A detailed clinical, histochemical, biochemical, and molecular genetic analysis was performed on two families with HCM to investigate the underlying mitochondrial defect.
  
  
  RESULTS
  Cardiac tissue from an affected child in the presenting family exhibited severe deficiencies of mitochondrial respiratory chain enzymes, whereas histochemical and biochemical studies of the skeletal muscle were normal. Mitochondrial DNA sequencing revealed an A4300G transition in the mitochondrial transfer ribonucleic acid (tRNA)(Ile) gene, which was shown to be homoplasmic by polymerase chain reaction/restriction fragment length polymorphism analysis in all samples from affected individuals and other maternal relatives. In a second family, previously reported as heteroplasmic for this base substitution, the mutation has subsequently been shown to be homoplasmic. The pathogenic role for this mutation was confirmed by high-resolution Northern blot analysis of heart tissue from both families, revealing very low steady-state levels of the mature mitochondrial tRNA(Ile).
  
  
  CONCLUSIONS
  This report documents, for the first time, that a homoplasmic mitochondrial tRNA mutation may cause maternally inherited HCM. It highlights the significant contribution that homoplasmic mitochondrial tRNA substitutions may play in the development of cardiac disease. A restriction of the biochemical defect to the affected tissue has important implications for the screening of patients with cardiomyopathy for mitochondrial disease.
authors.affiliation: Department of Neurology, The Medical School, Framlington Place, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Carla
authors.initials: C
authors.lastname: Giordano
authors.forename: Mercy M
authors.initials: MM
authors.lastname: Davidson
authors.forename: Giulia
authors.initials: G
authors.lastname: d'Amati
authors.forename: Hugh
authors.initials: H
authors.lastname: Bain
authors.forename: Christine M
authors.initials: CM
authors.lastname: Hayes
authors.forename: Helen
authors.initials: H
authors.lastname: Leonard
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Barron
authors.forename: Carlo
authors.initials: C
authors.lastname: Casali
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.forename: Robert N
authors.initials: RN
authors.lastname: Lightowlers
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiMauro
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics; D004579:Electron Transport; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000235:genetics* / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000235:genetics; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012313:RNA / Q000235:genetics*; D000077278:RNA, Mitochondrial; D012355:RNA, Transfer, Ile / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial; D000077278:RNA, Mitochondrial; D012355:RNA, Transfer, Ile; D012313:RNA