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

TitleFASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency.
Publication TypeJournal Article
Year of Publication2008
AuthorsGhezzi, D, Saada, A, D'Adamo, P, Fernandez-Vizarra, E, Gasparini, P, Tiranti, V, Elpeleg, O, Zeviani, M
JournalAm J Hum Genet
Volume83
Issue3
Pagination415-23
Date Published2008 Sep
ISSN1537-6605
KeywordsAnimals, Cercopithecus aethiops, Codon, Nonsense, COS Cells, Cytochrome-c Oxidase Deficiency, Female, Genetic Predisposition to Disease, HeLa Cells, Humans, Infant, Infant, Newborn, Male, Mitochondria, Mitochondrial Encephalomyopathies, Muscle, Skeletal, Pedigree, Protein-Serine-Threonine Kinases, Siblings
Abstract

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.

DOI10.1016/j.ajhg.2008.08.009
Alternate JournalAm. J. Hum. Genet.
Citation Key10.1016/j.ajhg.2008.08.009
PubMed ID18771761
PubMed Central IDPMC2556431
Grant ListGGP07019 / / Telethon / Italy