The mitochondrial DNA mutation T12297C affects a highly conserved nucleotide of tRNALeu(CUN) and is associated with dilated cardiomyopathy

Abstract

Mitochondrial DNA (mtDNA) mutations have been causally linked with cardiomyopathies, both dilated (DCM) and hypertrophic. We identified the T12297C mutation in the mtDNA-tRNA Leu(CUN) of a 36-year-old male patient diagnosed with DCM. The mutation was heteroplasmic, with high amount (88%) of mutant DNA in the myocardium, and was absent in normal (n=120) and disease (n=150) controls. It affects a highly conserved nucleotide (adjacent to the anticodon triplet) that allows the phospho-ribose backbone to turn and form the loop. The potential pathological role of T12297C mutation is further supported by its recent identification in another unrelated Italian family with DCM associated with endocardial fibroelastosis. In the variable loop of the same tRNA, our patient also carried the A12308G transition that is debated as pathological mutation or neutral polymorphism in progressive external ophthalmoplegia: the two defects could exert a synergistic effect on the tRNA structure and function. The endomyocardial biopsy study showed abnormal ring-like mitochondria and occasional cytochrome c oxydase negative myocytes. Overall, the heteroplasmy, the highly conserved position of the mutated nucleotide, the absence of the mutation in large series of diseased and normal controls, and the cardiac mitochondrial changes support a causative link of the mutation with the disease.

A comparative analysis approach to determining the pathogenicity of mitochondrial tRNA mutations

“…As shown in Table 2, this male died in infancy after presenting with cardiomyopathy, failure to thrive and lactic acidosis. Mitochondrial disease was suspected, and after excluding common point mutations and large-scale mtDNA rearrangements, whole genome sequencing revealed the previously reported [Grasso et al, 2001;Tessa et al, 1999] m.12297T>C mutation in mt-tRNA Leu(CUN) . This mutation affects a universally conserved position adjacent to the anticodon (Fig.…”

Dilated Form of Endocardial Fibroelastosis as a Result of Deficiency in Respiratory-Chain Complexes I and IV

“…5 From the pathological standpoint, very frequently, mitochondrial cardiomyopathy becomes manifest as a left ventricular concentric hypertrophy with, in isolated cases, an evolution into a dilated form that is only rarely associated with endocardial fibroelastosis. 1,7 Unfortunately, preclinical specific signatures of mitochondrial cardiomyopathy are scarce. In general, clinical suspicion for neonatal mitochondrial disorders with cardiomyopathy should arise in the presence of deafness, failure to thrive, lactic acidosis, and cardiomegaly with increasing signs of failure and/or arrhythmia, all of these sometimes within the spectrum of a multisystem presentation (mainly nervous system or skeletal muscle) and often with a clear maternal inheritance.…”

Mitochondrial A12308G polymorphism affects clinical features in patients with single mtDNA macrodeletion

“…6 Besides, a convincing association has been proved between the aging process and mtDNA haplogroups. 7,8 Our data suggest that the presence of the A12308G polymorph- Figure 1 Comparison of the A12308G-polymorphism's frequency in control subjects and different mitochondrialpatient groups: the diagrams are divided according to the absence (full) or presence (dot) of A9052G polymorphism.…”