A homoplasmic mtDNA variant can influence the phenotype of the pathogenic m.7472Cins MTTS1 mutation: are two mutations better than one?

Mutations in mitochondrial tRNA (mt-tRNA) genes are well recognized as a common cause of human disease, exhibiting a significant degree of clinical heterogeneity. While these differences are explicable, in part, by differences in the innate pathogenicity of the mutation, its distribution and abundance, other factors, including nuclear genetic background, mitochondrial DNA (mtDNA) haplotype and additional mtDNA mutations may influence the expression of mt-tRNA mutations. We describe the clinical, biochemical and molecular findings in a family with progressive myopathy, deafness and diabetes and striking respiratory chain abnormalities due to a well-characterized heteroplasmic mt-tRNA mutation in the mt-tRNA(Ser(UCN)) (MTTS1) gene. In addition to the m.7472Cins mutation, all individuals were homoplasmic for another variant, m.7472A > C, affecting the adjacent nucleotide in the mt-tRNA(Ser(UCN)) structure. In addition to available patient tissues, we have analysed transmitochondrial cybrid clones harbouring homoplasmic levels of m.7472A > C and varying levels of the m.7472Cins mutation in an attempt to clarify the precise role of the m.7472A > C transversion in the underlying respiratory chain abnormality. Evidence from both in vivo and in vitro studies demonstrate that the m.7472A > C is able to modify the expression of the m.7472Cins mutation and would suggest that it is not a neutral variant but appears to cause a biochemical defect by itself, confirming that homoplasmic mtDNA variants can modulate the phenotypic expression of pathogenic, heteroplasmic mtDNA mutations.

Motor neuron disease in a patient with a mitochondrial tRNAIle mutation.

OBJECTIVE: Motor neuron disease (MND) is a common neurodegenerative condition for which the underlying cause is uncertain in many patients. We identified a patient with clinical features suggestive of MND but additional cardiac and metabolic symptoms. We wished to determine if the clinical features were due to a mitochondrial DNA mutation. METHODS: The brain and spinal cord were studied using neuropathological techniques and agenetic defect investigated in individual neurons. RESULTS: There were atypical neuropathological features and genetic studies identified a pathogenic, heteroplasmic mitochondria tRNA(Ile) (4274T>C) mutation. INTERPRETATION: This case adds to the phenotypic variation seen in mitochondrial DNA disease but also highlights the potential role of mitochondrial dysfunction in the cause of MND.