title: Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance.
abstract: 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. pbonnen@bcm.edu
authors.forename: Penelope E
authors.initials: PE
authors.lastname: Bonnen
authors.forename: John W
authors.initials: JW
authors.lastname: Yarham
authors.forename: Arnaud
authors.initials: A
authors.lastname: Besse
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Eissa A
authors.initials: EA
authors.lastname: Faqeih
authors.forename: Ali Mohammad
authors.initials: AM
authors.lastname: Al-Asmari
authors.forename: Mohammad A M
authors.initials: MA
authors.lastname: Saleh
authors.forename: Wafaa
authors.initials: W
authors.lastname: Eyaid
authors.forename: Alrukban
authors.initials: A
authors.lastname: Hadeel
authors.forename: Langping
authors.initials: L
authors.lastname: He
authors.forename: Frances
authors.initials: F
authors.lastname: Smith
authors.forename: Shu
authors.initials: S
authors.lastname: Yau
authors.forename: Eve M
authors.initials: EM
authors.lastname: Simcox
authors.forename: Satomi
authors.initials: S
authors.lastname: Miwa
authors.forename: Taraka
authors.initials: T
authors.lastname: Donti
authors.forename: Khaled K
authors.initials: KK
authors.lastname: Abu-Amero
authors.forename: Lee-Jun
authors.initials: LJ
authors.lastname: Wong
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
authors.forename: Brett H
authors.initials: BH
authors.lastname: Graham
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Scott
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
mesh_terms: D000140:Acidosis, Lactic / Q000150:complications / Q000235:genetics / Q000473:pathology; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D020090:Chromosome Segregation / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D004579:Electron Transport / Q000235:genetics; D044783:F-Box Proteins / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D018628:Gene Dosage / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D017237:Mitochondrial Encephalomyopathies / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010085:Oxidative Phosphorylation; D010375:Pedigree; D021381:Protein Transport; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D044783:F-Box Proteins; D044767:Ubiquitin-Protein Ligases; C561936:FbxL4 protein, human