Woranontee Weraarpachai

Publications (5)95.83 Total impact

• Article: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.

  Woranontee Weraarpachai, Florin Sasarman, Tamiko Nishimura, Hana Antonicka, Karine Auré, Agnès Rötig, Anne Lombès, Eric A Shoubridge
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  ABSTRACT: We investigated a family in which the index subject presented with severe congenital lactic acidosis and dysmorphic features associated with a cytochrome c oxidase (COX)-assembly defect and a specific decrease in the synthesis of COX I, the subunit that nucleates COX assembly. Using a combination of microcell-mediated chromosome transfer, homozygosity mapping, and transcript profiling, we mapped the gene defect to chromosome 12 and identified a homozygous missense mutation (c.88G>A) in C12orf62. C12orf62 was not detectable by immunoblot analysis in subject fibroblasts, and retroviral expression of the wild-type C12orf62 cDNA rescued the biochemical phenotype. Furthermore, siRNA-mediated knockdown of C12orf 62 recapitulated the biochemical defect in control cells and exacerbated it in subject cells. C12orf62 is apparently restricted to the vertebrate lineage. It codes for a very small (6 kDa), uncharacterized, single-transmembrane protein that localizes to mitochondria and elutes in a complex of ∼110 kDa by gel filtration. COX I, II, and IV coimmunoprecipated with an epitope-tagged version of C12orf62, and 2D blue-native-polyacrylamide-gel-electrophoresis analysis of newly synthesized mitochondrial COX subunits in subject fibroblasts showed that COX assembly was impaired and that the nascent enzyme complex was unstable. We conclude that C12orf62 is required for coordination of the early steps of COX assembly with the synthesis of COX I.
  The American Journal of Human Genetics 01/2012; 90(1):142-51. · 10.60 Impact Factor
• Article: Mutation in subdomain G' of mitochondrial elongation factor G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle.

  Paulien Smits, Hana Antonicka, Peter M van Hasselt, Woranontee Weraarpachai, Wolfram Haller, Marieke Schreurs, Hanka Venselaar, Richard J Rodenburg, Jan A Smeitink, Lambert P van den Heuvel
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  ABSTRACT: The mitochondrial translation system is responsible for the synthesis of 13 proteins required for oxidative phosphorylation (OXPHOS), the major energy-generating process of our cells. Mitochondrial translation is controlled by various nuclear encoded proteins. In 27 patients with combined OXPHOS deficiencies, in whom complex II (the only complex that is entirely encoded by the nuclear DNA) showed normal activities, and mutations in the mitochondrial genome as well as polymerase gamma were excluded, we screened all mitochondrial translation factors for mutations. Here, we report a mutation in mitochondrial elongation factor G1 (GFM1) in a patient affected by severe, rapidly progressive mitochondrial encephalopathy. This mutation is predicted to result in an Arg250Trp substitution in subdomain G' of the elongation factor G1 protein and is presumed to hamper ribosome-dependent GTP hydrolysis. Strikingly, the decrease in enzyme activities of complex I, III and IV detected in patient fibroblasts was not found in muscle tissue. The OXPHOS system defects and the impairment in mitochondrial translation in fibroblasts were rescued by overexpressing wild-type GFM1, establishing the GFM1 defect as the cause of the fatal mitochondrial disease. Furthermore, this study evinces the importance of a thorough diagnostic biochemical analysis of both muscle tissue and fibroblasts in patients suspected to suffer from a mitochondrial disorder, as enzyme deficiencies can be selectively expressed.
  European journal of human genetics: EJHG 03/2011; 19(3):275-9. · 3.56 Impact Factor
• Article: Mutations in C12orf65 in patients with encephalomyopathy and a mitochondrial translation defect.

  Hana Antonicka, Elsebet Ostergaard, Florin Sasarman, Woranontee Weraarpachai, Flemming Wibrand, Anne Marie B Pedersen, Richard J Rodenburg, Marjo S van der Knaap, Jan A M Smeitink, Zofia M Chrzanowska-Lightowlers, Eric A Shoubridge
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  ABSTRACT: We investigated the genetic basis for a global and uniform decrease in mitochondrial translation in fibroblasts from patients in two unrelated pedigrees who developed Leigh syndrome, optic atrophy, and ophthalmoplegia. Analysis of the assembly of the oxidative phosphorylation complexes showed severe decreases of complexes I, IV, and V and a smaller decrease in complex III. The steady-state levels of mitochondrial mRNAs, tRNAs, and rRNAs were not reduced, nor were those of the mitochondrial translation elongation factors or the protein components of the mitochondrial ribosome. Using homozygosity mapping, we identified a 1 bp deletion in C12orf65 in one patient, and DNA sequence analysis showed a different 1 bp deletion in the second patient. Both mutations predict the same premature stop codon. C12orf65 belongs to a family of four mitochondrial class I peptide release factors, which also includes mtRF1a, mtRF1, and Ict1, all characterized by the presence of a GGQ motif at the active site. However, C12orf65 does not exhibit peptidyl-tRNA hydrolase activity in an in vitro assay with bacterial ribosomes. We suggest that it might play a role in recycling abortive peptidyl-tRNA species, released from the ribosome during the elongation phase of translation.
  The American Journal of Human Genetics 07/2010; 87(1):115-22. · 10.60 Impact Factor
• Source

  Available from: Jürgen Seeger

  Article: Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome.

  Woranontee Weraarpachai, Hana Antonicka, Florin Sasarman, Jürgen Seeger, Bertold Schrank, Jill E Kolesar, Hanns Lochmüller, Mario Chevrette, Brett A Kaufman, Rita Horvath, Eric A Shoubridge
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  ABSTRACT: Defects in mitochondrial translation are among the most common causes of mitochondrial disease, but the mechanisms that regulate mitochondrial translation remain largely unknown. In the yeast Saccharomyces cerevisiae, all mitochondrial mRNAs require specific translational activators, which recognize sequences in 5' UTRs and mediate translation. As mammalian mitochondrial mRNAs do not have significant 5' UTRs, alternate mechanisms must exist to promote translation. We identified a specific defect in the synthesis of the mitochondrial DNA (mtDNA)-encoded COX I subunit in a pedigree segregating late-onset Leigh syndrome and cytochrome c oxidase (COX) deficiency. We mapped the defect to chromosome 17q by functional complementation and identified a homozygous single-base-pair insertion in CCDC44, encoding a member of a large family of hypothetical proteins containing a conserved DUF28 domain. CCDC44, renamed TACO1 for translational activator of COX I, shares a notable degree of structural similarity with bacterial homologs, and our findings suggest that it is one of a family of specific mammalian mitochondrial translational activators.
  Nature Genetics 08/2009; 41(7):833-7. · 35.53 Impact Factor
• Article: Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome

  Woranontee Weraarpachai, Hana Antonicka, Florin Sasarman, J|[uuml]|rgen Seeger, Bertold Schrank, Jill E Kolesar, Hanns Lochm|[uuml]|ller, Mario Chevrette, Brett A Kaufman, Rita Horvath, Eric A Shoubridge
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  ABSTRACT: Defects in mitochondrial translation are among the most common causes of mitochondrial disease
  Nature Genetics 06/2009; 41(7):833-837. · 35.53 Impact Factor