Abg-Kamaludin D

Chrzanowska-Lightowlers Z

Lightowlers R

Mcfarland R

Rorbach J

Taylor R

Tuppen H

Turnbull D

Yusoff A

Phenotypic diversity associated with pathogenic mutations of the human mitochondrial genome (mtDNA) has often been explained by unequal segregation of the mutated and wild-type genomes (heteroplasmy). However, this simple hypothesis cannot explain the tissue specificity of disorders caused by homoplasmic mtDNA mutations. We have previously associated a homoplasmic point mutation (1624C &gt; T) in MTTV with a profound metabolic disorder that resulted in the neonatal deaths of numerous siblings. Affected tissues harboured a marked biochemical defect in components of the mitochondrial respiratory chain, presumably due to the extremely low (&lt;1%) steady-state levels of mt-tRNAVal. In primary myoblasts and trans mitochondrial cybrids established from the proband (index case) and offspring, the marked respiratory deficiency was lost and steady-state levels of the mutated mt-tRNAVal were greater than in the biopsy material, but were still an order of magnitude lower than in control myoblasts. We present evidence that the generalized decrease in steady-state mt-tRNAVal observed in the homoplasmic 1624C &gt; T-cell lines is caused by a rapid degradation of the deacylated form of the abnormal mt-tRNAVal. By both establishing the identity of the human mitochondrial valyl-tRNA synthetase then inducing its overexpression in trans mitochondrial cell lines, we have been able to partially restore steady-state levels of the mutated mt-tRNAVal, consistent with an increased stability of the charged mt-tRNA. These data indicate that variations in the levels of VARS2L between tissue types and patients could underlie the difference in clinical presentation between individuals homoplasmic for the 1624C &gt; T mutation. \ua9 2008 The Author(s)

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Overexpression of human mitochondrial valyl tRNA synthetase can partially restore levels of cognate mt-tRNAVal carrying the pathogenic C25U mutation

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Overexpression of human mitochondrial valyl tRNA synthetase can partially restore levels of cognate mt-tRNAVal carrying the pathogenic C25U mutation

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