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CLINICAL RESEARCH

A homoplasmic mitochondrial transfer Ribonucleic Acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy

Robert W. Taylor, PhD^*, Carla Giordano, MD, Mercy M. Davidson, PhD, Giulia d’Amati, MD, PhD, Hugh Bain, MD, Christine M. Hayes, BSc^*, Helen Leonard, MD, Martin J. Barron, PhD^*, Carlo Casali, MD, PhD^||, Filippo M. Santorelli, MD^¶, Michio Hirano, MD, Robert N. Lightowlers, PhD^*, Salvatore DiMauro, MD and Douglass M. Turnbull, MD, PhD^*,*

^* Department of Neurology, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York, USA
Department of Paediatric Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom
Dipartimento di Medicina Sperimentale e Patologia, Newcastle upon Tyne, United Kingdom
^|| Istituto di Clinica delle Malattie Nervose e Mentali, Newcastle upon Tyne, United Kingdom
^¶ Molecular Medicine, Children’s Hospital "Bambino Gesù," Università di Roma-La Sapienza, Rome, Italy

Manuscript received November 21, 2002; accepted January 22, 2003.

^* Reprint requests and correspondence: Prof. Douglass M. Turnbull, Department of Neurology, The Medical School, Framlington Place, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, United Kingdom.
d.m.turnbull{at}ncl.ac.uk

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 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.

Abbreviations and Acronyms   COX   cytochrome c oxidase   HCM   hypertrophic cardiomyopathy   LHON   Leber’s hereditary optic neuropathy   LV   left ventricle or ventricular   mtDNA   mitochondrial deoxyribonucleic acid   mt-tRNAIle   mitochondrial transfer ribonucleic acid gene for isoleucine   PCR   polymerase chain reaction   RFLP   restriction fragment length polymorphism   SDH   succinate dehydrogenase

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