A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy

Robert W. Taylor, Carla Giordano, Mercy M. Davidson, Giulia D'Amati, Hugh Bain, Christine M. Hayes, Helen Leonard, Martin J. Barron, Carlo Casali, Filippo M. Santorelli, Michio Hirano, Robert N. Lightowlers, Salvatore DiMauro, Douglass M. Turnbull

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Abstract

OBJECTIVES: 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 tRNAIle. 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.

Original languageEnglish
Pages (from-to)1786-1796
Number of pages11
JournalJournal of the American College of Cardiology
Volume41
Issue number10
DOIs
Publication statusPublished - May 21 2003

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Hypertrophic Cardiomyopathy
Transfer RNA
Mutation
Mitochondrial Diseases
Cardiomyopathies
Molecular Biology
RNA, Transfer, Ile
Familial Hypertrophic Cardiomyopathy
Mitochondrial Genome
DNA
Mitochondrial DNA
DNA Sequence Analysis
Restriction Fragment Length Polymorphisms
Northern Blotting
Virulence
Heart Diseases
Skeletal Muscle
Mothers
Maternal Inheritance
Genome

ASJC Scopus subject areas

  • Nursing(all)

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A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. / Taylor, Robert W.; Giordano, Carla; Davidson, Mercy M.; D'Amati, Giulia; Bain, Hugh; Hayes, Christine M.; Leonard, Helen; Barron, Martin J.; Casali, Carlo; Santorelli, Filippo M.; Hirano, Michio; Lightowlers, Robert N.; DiMauro, Salvatore; Turnbull, Douglass M.

In: Journal of the American College of Cardiology, Vol. 41, No. 10, 21.05.2003, p. 1786-1796.

Research output: Contribution to journalArticle

Taylor, RW, Giordano, C, Davidson, MM, D'Amati, G, Bain, H, Hayes, CM, Leonard, H, Barron, MJ, Casali, C, Santorelli, FM, Hirano, M, Lightowlers, RN, DiMauro, S & Turnbull, DM 2003, 'A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy', Journal of the American College of Cardiology, vol. 41, no. 10, pp. 1786-1796. https://doi.org/10.1016/S0735-1097(03)00300-0
Taylor, Robert W. ; Giordano, Carla ; Davidson, Mercy M. ; D'Amati, Giulia ; Bain, Hugh ; Hayes, Christine M. ; Leonard, Helen ; Barron, Martin J. ; Casali, Carlo ; Santorelli, Filippo M. ; Hirano, Michio ; Lightowlers, Robert N. ; DiMauro, Salvatore ; Turnbull, Douglass M. / A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. In: Journal of the American College of Cardiology. 2003 ; Vol. 41, No. 10. pp. 1786-1796.
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T1 - A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy

AU - Taylor, Robert W.

AU - Giordano, Carla

AU - Davidson, Mercy M.

AU - D'Amati, Giulia

AU - Bain, Hugh

AU - Hayes, Christine M.

AU - Leonard, Helen

AU - Barron, Martin J.

AU - Casali, Carlo

AU - Santorelli, Filippo M.

AU - Hirano, Michio

AU - Lightowlers, Robert N.

AU - DiMauro, Salvatore

AU - Turnbull, Douglass M.

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N2 - OBJECTIVES: 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 tRNAIle. 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.

AB - OBJECTIVES: 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 tRNAIle. 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.

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