Biochemical characterization of the mitochondrial tRNASer(UCN) T7511C mutation associated with nonsyndromic deafness
AUTOR(ES)
Li, Xiaoming
FONTE
Oxford University Press
RESUMO
We report here the biochemical characterization of the deafness-associated mitochondrial tRNASer(UCN) T7511C mutation, in conjunction with homoplasmic ND1 T3308C and tRNAAla T5655C mutations using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from an African family into human mtDNA-less (ρ°) cells. Three cybrids derived from an affected matrilineal relative carrying the homoplasmic T7511C mutation, exhibited ∼75% decrease in the tRNASer(UCN) level, compared with three control cybrids. This amount of reduction in the tRNASer(UCN) level is below a proposed threshold to support a normal rate of mitochondrial protein synthesis in lymphoblastoid cell lines. This defect is likely a primary contributor to ∼52% reduction in the rate of mitochondrial protein synthesis and marked defects in respiration and growth properties in galactose-containing medium. Interestingly, the T5655C mutation produces ∼50% reduction in the tRNAAla level in mutant cells. Strikingly, the T3308C mutation causes a significant decrease both in the amount of ND1 mRNA and co-transcribed tRNALeu(UUR) in mutant cells. Thus, mitochondrial dysfunctions caused by the T5655C and T3308C mutations may modulate the phenotypic manifestation of the T7511C mutation. These observations imply that a combination of the T7511C mutation with two mtDNA mutations accounts for the high penetrance of deafness in this family.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=373379Documentos Relacionados
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