%0 Journal Article %J Am J Hum Genet %D 2013 %T Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance. %A Bonnen, Penelope E %A Yarham, John W %A Besse, Arnaud %A Wu, Ping %A Faqeih, Eissa A %A Al-Asmari, Ali Mohammad %A Saleh, Mohammad A M %A Eyaid, Wafaa %A Hadeel, Alrukban %A He, Langping %A Smith, Frances %A Yau, Shu %A Simcox, Eve M %A Miwa, Satomi %A Donti, Taraka %A Abu-Amero, Khaled K %A Wong, Lee-Jun %A Craigen, William J %A Graham, Brett H %A Scott, Kenneth L %A McFarland, Robert %A Taylor, Robert W %K Acidosis, Lactic %K Base Sequence %K Child %K Child, Preschool %K Chromosome Segregation %K DNA, Mitochondrial %K Electron Transport %K F-Box Proteins %K Female %K Fibroblasts %K Gene Dosage %K Genes, Recessive %K Genetic Predisposition to Disease %K Humans %K Infant %K Infant, Newborn %K Male %K Mitochondrial Encephalomyopathies %K Molecular Sequence Data %K Muscle, Skeletal %K Mutation %K Oxidative Phosphorylation %K Pedigree %K Protein Transport %K Ubiquitin-Protein Ligases %X

Nuclear genetic disorders causing mitochondrial DNA (mtDNA) depletion are clinically and genetically heterogeneous, and the molecular etiology remains undiagnosed in the majority of cases. Through whole-exome sequencing, we identified recessive nonsense and splicing mutations in FBXL4 segregating in three unrelated consanguineous kindreds in which affected children present with a fatal encephalopathy, lactic acidosis, and severe mtDNA depletion in muscle. We show that FBXL4 is an F-box protein that colocalizes with mitochondria and that loss-of-function and splice mutations in this protein result in a severe respiratory chain deficiency, loss of mitochondrial membrane potential, and a disturbance of the dynamic mitochondrial network and nucleoid distribution in fibroblasts from affected individuals. Expression of the wild-type FBXL4 transcript in cell lines from two subjects fully rescued the levels of mtDNA copy number, leading to a correction of the mitochondrial biochemical deficit. Together our data demonstrate that mutations in FBXL4 are disease causing and establish FBXL4 as a mitochondrial protein with a possible role in maintaining mtDNA integrity and stability.

%B Am J Hum Genet %V 93 %P 471-81 %8 2013 Sep 05 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/23993193?dopt=Abstract %R 10.1016/j.ajhg.2013.07.017