A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy.
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.
Taylor
Robert W
RW
Department of Neurology, The Medical School, Framlington Place, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK.
Giordano
Carla
C
Davidson
Mercy M
MM
d'Amati
Giulia
G
Bain
Hugh
H
Hayes
Christine M
CM
Leonard
Helen
H
Barron
Martin J
MJ
Casali
Carlo
C
Santorelli
Filippo M
FM
Hirano
Michio
M
Lightowlers
Robert N
RN
DiMauro
Salvatore
S
Turnbull
Douglass M
DM
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
D004272:DNA, Mitochondrial; D000077278:RNA, Mitochondrial; D012355:RNA, Transfer, Ile; D012313:RNA