FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency

Am J Hum Genet. 2008 Sep;83(3):415-23. doi: 10.1016/j.ajhg.2008.08.009. Epub 2008 Sep 4.


In two siblings we found a mitochondrial encephalomyopathy, characterized by developmental delay, hemiplegia, convulsions, asymmetrical brain atrophy, and low cytochrome c oxidase (COX) activity in skeletal muscle. The disease locus was identified on chromosome 2 by homozygosity mapping; candidate genes were prioritized for their known or predicted mitochondrial localization and then sequenced in probands and controls. A homozygous nonsense mutation in the KIAA0971 gene segregated with the disease in the proband family. The corresponding protein is known as fas activated serine-threonine kinase domain 2, FASTKD2. Confocal immunofluorescence colocalized a tagged recombinant FASTKD2 protein with mitochondrial markers, and membrane-potential-dependent in vitro mitochondrial import was demonstrated in isolated mitochondria. In staurosporine-induced-apoptosis experiments, decreased nuclear fragmentation was detected in treated mutant versus control fibroblasts. In conclusion, we found a loss-of-function mutation in a gene segregating with a peculiar mitochondrial encephalomyopathy associated with COX deficiency in skeletal muscle. The corresponding protein is localized in the mitochondrial inner compartment. Preliminary data indicate that FASTKD2 plays a role in mitochondrial apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Codon, Nonsense*
  • Cytochrome-c Oxidase Deficiency / genetics*
  • Cytochrome-c Oxidase Deficiency / metabolism
  • Female
  • Genetic Predisposition to Disease*
  • HeLa Cells
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mitochondria / metabolism
  • Mitochondrial Encephalomyopathies / genetics*
  • Mitochondrial Encephalomyopathies / metabolism
  • Muscle, Skeletal / metabolism*
  • Pedigree
  • Protein Serine-Threonine Kinases / genetics*
  • Siblings


  • Codon, Nonsense
  • FASTKD2 protein, human
  • Protein Serine-Threonine Kinases