TY - JOUR
T1 - A homoplasmic mtDNA variant can influence the phenotype of the pathogenic m.7472Cins MTTS1 mutation
T2 - Are two mutations better than one?
AU - Swalwell, Helen
AU - Blakely, Emma L.
AU - Sutton, Ruth
AU - Tonska, Kasia
AU - Elstner, Matthias
AU - He, Langping
AU - Taivassalo, Tanja
AU - Burns, Dennis K.
AU - Turnbull, Douglass M.
AU - Haller, Ronald G.
AU - Davidson, Mercy M.
AU - Taylor, Robert W.
N1 - Funding Information:
We thank Christine Hayes, Karen Ayyad, Nadine Romain and Winsome Walker for excellent technical assistance. This work was supported by grants from the Muscular Dystrophy Association and the United Mitochondrial Disease Foundation (to TT and RGH), the US National Institutes of Health (to MMD) and The Wellcome Trust, Muscular Dystrophy Campaign and Newcastle upon Tyne Hospitals NHS Foundation Trust (to DMT and RWT).
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
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U2 - 10.1038/ejhg.2008.65
DO - 10.1038/ejhg.2008.65
M3 - Article
C2 - 18398437
AN - SCOPUS:53249132725
SN - 1018-4813
VL - 16
SP - 1265
EP - 1274
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 10
ER -