Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.

TitleMutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.
Publication TypeJournal Article
Year of Publication2013
AuthorsGai, X, Ghezzi, D, Johnson, MA, Biagosch, CA, Shamseldin, HE, Haack, TB, Reyes, A, Tsukikawa, M, Sheldon, CA, Srinivasan, S, Gorza, M, Kremer, LS, Wieland, T, Strom, TM, Polyak, E, Place, E, Consugar, M, Ostrovsky, J, Vidoni, S, Robinson, AJ, Wong, L-J, Sondheimer, N, Salih, MA, Al-Jishi, E, Raab, CP, Bean, C, Furlan, F, Parini, R, Lamperti, C, Mayr, JA, Konstantopoulou, V, Huemer, M, Pierce, EA, Meitinger, T, Freisinger, P, Sperl, W, Prokisch, H, Alkuraya, FS, Falk, MJ, Zeviani, M
JournalAm J Hum Genet
Date Published2013 Sep 05
KeywordsAge of Onset, Child, Child, Preschool, Chromosomes, Human, Pair 6, DNA, Complementary, F-Box Proteins, Female, Fibroblasts, Genes, Recessive, Genetic Predisposition to Disease, HEK293 Cells, Humans, Infant, Infant, Newborn, Male, Mitochondria, Mitochondrial Encephalomyopathies, Mitochondrial Proteins, Muscle, Skeletal, Mutant Proteins, Mutation, Oxidative Phosphorylation, Pedigree, Protein Transport, Subcellular Fractions, Syndrome, Ubiquitin-Protein Ligases

Whole-exome sequencing and autozygosity mapping studies, independently performed in subjects with defective combined mitochondrial OXPHOS-enzyme deficiencies, identified a total of nine disease-segregating FBXL4 mutations in seven unrelated mitochondrial disease families, composed of six singletons and three siblings. All subjects manifested early-onset lactic acidemia, hypotonia, and developmental delay caused by severe encephalomyopathy consistently associated with progressive cerebral atrophy and variable involvement of the white matter, deep gray nuclei, and brainstem structures. A wide range of other multisystem features were variably seen, including dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosis, seizures, and episodic metabolic failure. Mitochondrial respiratory chain deficiency was present in muscle or fibroblasts of all tested individuals, together with markedly reduced oxygen consumption rate and hyperfragmentation of the mitochondrial network in cultured cells. In muscle and fibroblasts from several subjects, substantially decreased mtDNA content was observed. FBXL4 is a member of the F-box family of proteins, some of which are involved in phosphorylation-dependent ubiquitination and/or G protein receptor coupling. We also demonstrate that FBXL4 is targeted to mitochondria and localizes in the intermembrane space, where it participates in an approximately 400 kDa protein complex. These data strongly support a role for FBXL4 in controlling bioenergetic homeostasis and mtDNA maintenance. FBXL4 mutations are a recurrent cause of mitochondrial encephalomyopathy onset in early infancy.

Alternate JournalAm. J. Hum. Genet.
Citation Key10.1016/j.ajhg.2013.07.016
PubMed ID23993194
PubMed Central IDPMC3769923
Grant ListP30EY014104 / EY / NEI NIH HHS / United States
R03 DK082521 / DK / NIDDK NIH HHS / United States
R03-DK082446 / DK / NIDDK NIH HHS / United States
1G20RR030939 / RR / NCRR NIH HHS / United States
R01-EY012910 / EY / NEI NIH HHS / United States
GGP11139 / / Telethon / Italy
322424 / / European Research Council / International
G20 RR030939 / RR / NCRR NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
R01 EY012910 / EY / NEI NIH HHS / United States
MC_U105674181 / / Medical Research Council / United Kingdom
P30 EY014104 / EY / NEI NIH HHS / United States
UL1 RR024134 / RR / NCRR NIH HHS / United States
(UL1-RR-024134 / RR / NCRR NIH HHS / United States