title: FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency.
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.
authors.affiliation: Division of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.forename: Pio
authors.initials: P
authors.lastname: D'Adamo
authors.forename: Erika
authors.initials: E
authors.lastname: Fernandez-Vizarra
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasparini
authors.forename: Valeria
authors.initials: V
authors.lastname: Tiranti
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D018389:Codon, Nonsense; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D035781:Siblings
chemical_list: D018389:Codon, Nonsense; C532222:FASTKD2 protein, human; D017346:Protein Serine-Threonine Kinases
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