Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance

Am J Hum Genet. 2013 Sep 5;93(3):471-81. doi: 10.1016/j.ajhg.2013.07.017. Epub 2013 Aug 29.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidosis, Lactic / complications
  • Acidosis, Lactic / genetics
  • Acidosis, Lactic / pathology
  • Base Sequence
  • Child
  • Child, Preschool
  • Chromosome Segregation / genetics
  • DNA, Mitochondrial / genetics*
  • Electron Transport / genetics
  • F-Box Proteins / chemistry
  • F-Box Proteins / genetics*
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Dosage / genetics
  • Genes, Recessive / genetics
  • Genetic Predisposition to Disease*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mitochondrial Encephalomyopathies / complications
  • Mitochondrial Encephalomyopathies / genetics*
  • Mitochondrial Encephalomyopathies / pathology
  • Molecular Sequence Data
  • Muscle, Skeletal / pathology
  • Mutation / genetics*
  • Oxidative Phosphorylation
  • Pedigree
  • Protein Transport
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / genetics*


  • DNA, Mitochondrial
  • F-Box Proteins
  • Ubiquitin-Protein Ligases
  • FbxL4 protein, human

Supplementary concepts

  • Mitochondrial encephalopathy