Alternative titles; symbols
HGNC Approved Gene Symbol: FBXL4
SNOMEDCT: 765403009;
Cytogenetic location: 6q16.1-q16.2 Genomic coordinates (GRCh38) : 6:98,868,535-98,947,946 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q16.1-q16.2 | Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) | 615471 | Autosomal recessive | 3 |
The F box, named after cyclin F (CCNF; 600227), in which it was originally observed, is an approximately 40-amino acid motif that binds SKP1 (601434). F-box proteins, such as FBXL4, are components of modular E3 ubiquitin protein ligases called SCFs (SKP1, cullin (see 603134), F-box proteins), which function in phosphorylation-dependent ubiquitination.
Using a yeast 2-hybrid screen with SKP1 as bait, followed by searching sequence databases, Winston et al. (1999) and Cenciarelli et al. (1999) identified 33 mammalian and 26 human F-box proteins, respectively. These contained C termini with leucine-rich repeats (FBXLs, e.g., SKP2 (601436)), WD40 domains (FBXWs, e.g., BTRCP (603482)), or no recognizable motifs (FBXOs, e.g., CCNF). Using RT-PCR analysis, Winston et al. (1999) detected FBXL4 expression in heart, kidney, liver, lung, pancreas, and placenta, but not in skeletal muscle. Immunofluorescence microscopy demonstrated both nuclear and cytoplasmic expression.
By searching sequence databases, Ilyin et al. (2000) identified a cDNA encoding FBXL4, which they referred to as FBL5. The deduced 621-amino acid protein contains at least 9 leucine-rich repeats.
Jin et al. (2004) reported that the FBXL4 protein contains an F box in its N-terminal half, followed by 11 leucine-rich repeats.
By computational analysis followed by immunolocalization studies, Bonnen et al. (2013) demonstrated that the FBXL4 protein localizes to the mitochondria via an N-terminal mitochondrial localization signal. Gai et al. (2013) also found FBXL4 localization to the mitochondria in several cell lines using immunofluorescence studies; nuclear localization was not observed. The protein appeared to be present in the intermembrane space.
Based on its inclusion within a mapped clone, Ilyin et al. (2000) mapped the FBXL4 gene to 6q16.1-q16.3.
Jin et al. (2004) stated that the mouse Fbxl4 gene maps to chromosome 4A3.
Gai et al. (2013) demonstrated that FBXL4 is targeted to mitochondria and localizes within the intermembrane space. Immunoblot analysis showed that it is present in an approximately 400-kD quaternary protein complex.
In affected individuals from 3 consanguineous Arabian families with encephalomyopathic mitochondrial DNA depletion syndrome-13 (MTDPS13; 615471), Bonnen et al. (2013) identified 3 different homozygous mutations in the FBXL4 gene (see, e.g., 605654.0001 and 605654.0002). The mutations, which were found by whole-exome sequencing in the probands, segregated with the disorder in the families. Two of the mutations were truncating mutations. The patients presented at birth or in early infancy with global developmental delay, hypotonia, and persistent lactic acidosis. More variable features included facial dysmorphism, congenital cataracts, and brain atrophy. All patients except 1 died in early childhood. Patient skeletal muscle biopsies and fibroblasts showed defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion. Expression of wildtype FBXL4 in patient cells rescued the mitochondrial biochemical defects and mtDNA depletion. The findings suggested that FBXL4 plays an important role in the maintenance of mtDNA.
In 9 patients from 7 families with MTDPS13, Gai et al. (2013) identified biallelic mutations in the FBXL4 gene (see, e.g., 605654.0003-605654.0005). Most patients presented shortly after birth with lactic acidosis, often with hyperammonemia and signs of renal tubular acidosis. All patients showed severe psychomotor delay with hypotonia and failure to thrive. Three children died in infancy from metabolic decompensation during intercurrent infections. Brain MRI showed global brain atrophy, thin corpus callosum, and altered signals in the supratentorial white matter with variable involvement of the basal ganglia, thalami, and infratentorial structures. Patient muscle homogenates or isolated mitochondria showed variably decreased activities of the mitochondrial respiratory chain complexes as well as decreased mtDNA content. Cultured skin fibroblasts had reduced maximal oxygen consumption rate and increased fragmentation of the mitochondrial network. At least 1 patient cell line studied showed a significant reduction of the mitochondrial membrane potential. These defects could be rescued by expression of wildtype FBXL4 in patient cells. The findings indicated that FBXL4 is necessary for the homeostasis of mitochondrial bioenergetics.
In 5 affected members of a highly consanguineous Arabian family with fatal mitochondrial DNA depletion syndrome-13 (MTDPS13; 615471), Bonnen et al. (2013) identified a homozygous c.1555C-T transition in the FBXL4 gene, resulting in a gln519-to-ter (Q519X) substitution in the C-terminal LRR domain. The mutation was found by whole-exome sequencing of the proband and showed complete segregation with the disorder in the family. The variant was not present in the NHLBI Exome Sequencing Project or 1000 Genomes Project databases, or in 408 ethnically matched control chromosomes.
In a child, born of consanguineous Arabian parents, with fatal MTDPS13 (615471), Bonnen et al. (2013) identified a homozygous c.1303C-T transition in the FBXL4 gene, resulting in an arg435-to-ter (R435X) substitution. The mutation was found by whole-exome sequencing and segregated with the disorder in the family. The variant was not present in the 1000 Genomes Project database or in 408 ethnically matched controls; it was found in 1 of 13,005 chromosomes in the NHLBI Exome Sequencing Project.
In a 4-year-old boy, born of consanguineous Saudi Arabian parents, with MTDPS13 (615471), Gai et al. (2013) identified a homozygous c.1703G-C transversion in the FBXL4 gene, resulting in a gly568-to-ala (G568A) substitution at a highly conserved residue in the LRR domain. The mutation was found by homozygosity mapping followed by whole-exome sequencing. The mutation was not present in 242 Saudi exomes, in 4,500 in-house European control chromosomes, or in the Exome Variant Server database.
In 3 sibs, born of consanguineous Saudi Arabian parents, with MTDPS13 (615471), Gai et al. (2013) identified a homozygous c.1444C-T transition in the FBXL4 gene, resulting in an arg482-to-trp (R481W) substitution at a highly conserved residue in the LRR domain. The mutation was found by homozygosity mapping followed by whole-exome sequencing. It was not present in 242 Saudi exomes, in 4,500 in-house European control chromosomes, or in the Exome Variant Server database.
In an Albanian male infant with MTDPS13 (615471), Gai et al. (2013) identified a homozygous c.1694A-G transition in the FBXL4 gene, resulting in an asp565-to-gly (D565G) substitution at a highly conserved residue in the LRR domain. The mutation was found by whole-exome sequencing and was not present in 4,500 in-house European control chromosomes or in the Exome Variant Server database.
Bonnen, P. E., Yarham, J. W., Besse, A., Wu, P., Faqeih, E. A., Al-Asmari, A. M., Saleh, M. A. M., Eyaid, W., Hadeel, A., He, L., Smith, F., Yau, S., and 10 others. Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance. Am. J. Hum. Genet. 93: 471-481, 2013. Note: Erratum: Am. J. Hum. Genet. 93: 773 only, 2013. [PubMed: 23993193] [Full Text: https://doi.org/10.1016/j.ajhg.2013.07.017]
Cenciarelli, C., Chiaur, D. S., Guardavaccaro, D., Parks, W., Vidal, M., Pagano, M. Identification of a family of human F-box proteins. Curr. Biol. 9: 1177-1179, 1999. [PubMed: 10531035] [Full Text: https://doi.org/10.1016/S0960-9822(00)80020-2]
Gai, X., Ghezzi, D., Johnson, M. A., Biagosch, C. A., Shamseldin, H. E., Haack, T. B., Reyes, A., Tsukikawa, M., Sheldon, C. A., Srinivasan, S., Gorza, M., Kremer, L. S., and 28 others. Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy. Am. J. Hum. Genet. 93: 482-495, 2013. [PubMed: 23993194] [Full Text: https://doi.org/10.1016/j.ajhg.2013.07.016]
Ilyin, G. P., Rialland, M., Pigeon, C., Guguen-Guillouzo, C. cDNA cloning and expression analysis of new members of the mammalian F-box protein family. Genomics 67: 40-47, 2000. [PubMed: 10945468] [Full Text: https://doi.org/10.1006/geno.2000.6211]
Jin, J., Cardozo, T., Lovering, R. C., Elledge, S. J., Pagano, M., Harper, J. W. Systematic analysis and nomenclature of mammalian F-box proteins. Genes Dev. 18: 2573-2580, 2004. [PubMed: 15520277] [Full Text: https://doi.org/10.1101/gad.1255304]
Winston, J. T., Koepp, D. M., Zhu, C., Elledge, S. J., Harper, J. W. A family of mammalian F-box proteins. Curr. Biol. 9: 1180-1182, 1999. [PubMed: 10531037] [Full Text: https://doi.org/10.1016/S0960-9822(00)80021-4]