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

Helen Swalwell, Emma L. Blakely, Ruth Sutton, Kasia Tonska, Matthias Elstner, Langping He, Tanja Taivassalo, Dennis K. Burns, Douglass M. Turnbull, Ronald G. Haller, Mercy M. Davidson, Robert W. Taylor

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

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-tRNASer(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-tRNASer(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.

Original languageEnglish (US)
Pages (from-to)1265-1274
Number of pages10
JournalEuropean Journal of Human Genetics
Volume16
Issue number10
DOIs
StatePublished - Oct 10 2008

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Swalwell, H., Blakely, E. L., Sutton, R., Tonska, K., Elstner, M., He, L., Taivassalo, T., Burns, D. K., Turnbull, D. M., Haller, R. G., Davidson, M. M., & Taylor, R. W. (2008). A homoplasmic mtDNA variant can influence the phenotype of the pathogenic m.7472Cins MTTS1 mutation: Are two mutations better than one? European Journal of Human Genetics, 16(10), 1265-1274. https://doi.org/10.1038/ejhg.2008.65