FBXL4

Chr 6AR

F-box and leucine rich repeat protein 4

Also known as: FBL4, FBL5, MTDPS13

NCBI Gene: 26235ENSG00000112234UniProt: Q9UKA2

This gene encodes a member of the F-box protein family, which are characterized by an approximately 40 amino acid motif, the F-box. F-box proteins constitute one subunit of modular E3 ubiquitin ligase complexes, called SCF complexes, which function in phosphorylation-dependent ubiquitination. The F-box domain mediates protein-protein interactions and binds directly to S-phase kinase-associated protein 1. In addition to an F-box domain, the encoded protein contains at least 9 tandem leucine-rich repeats. The ubiquitin ligase complex containing the encoded protein may function in cell-cycle control by regulating levels of lysine-specific demethylase 4A. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

Primary Disease Associations & Inheritance

Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type)MIM #615471
AR
673
ClinVar variants
61
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— FBXL4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
61 Pathogenic / Likely Pathogenic· 207 VUS of 673 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.92LOEUF
pLI 0.000
Z-score 1.90
OE 0.61 (0.42–0.92)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.55Z-score
OE missense 0.91 (0.83–1.01)
299 obs / 327.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.61 (0.42–0.92)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.83–1.01)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01
0≤1.21.6
LoF obs/exp: 17 / 27.8Missense obs/exp: 299 / 327.2Syn Z: -0.10

ClinVar Variant Classifications

673 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33
Likely Pathogenic28
VUS207
Likely Benign88
Benign13
Conflicting22
33
Pathogenic
28
Likely Pathogenic
207
VUS
88
Likely Benign
13
Benign
22
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
0
26
0
33
Likely Pathogenic
11
8
9
0
28
VUS
3
169
19
16
207
Likely Benign
0
1
38
49
88
Benign
0
0
13
0
13
Conflicting
—22
Total2117810565391

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

FBXL4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

FBXL4-related fatal encephalopathy, lactic acidosis, and severe mitochondrial DNA depletion in muscle

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type)

MIM #615471

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mitochondrial DNA maintenance defects.
El-Hattab AW et al.·Biochim Biophys Acta Mol Basis Dis
2017Review
Molecular and clinical spectra of FBXL4 deficiency.
El-Hattab AW et al.·Hum Mutat
2017Review
FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors.
Nguyen-Dien GT et al.·EMBO J
2023
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
Prenatal FBXL4-Associated Mitochondrial DNA Depletion Syndrome-13: A New Case and Review of the Literature.
Ros A et al.·Prenat Diagn
2025Review
FBXL4 deficiency increases mitochondrial removal by autophagy.
Alsina D et al.·EMBO Mol Med
2020
Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations.
Huemer M et al.·J Inherit Metab Dis
2015
Genome sequencing reanalysis increases the diagnostic yield in dystonia.
Fellner A et al.·Parkinsonism Relat Disord
2024
Dichloroacetate improves mitochondrial function, physiology, and morphology in FBXL4 disease models.
Lavorato M et al.·JCI Insight
2022Functional
Characterization of the C584R variant in the mtDNA depletion syndrome gene FBXL4, reveals a novel role for FBXL4 as a regulator of mitochondrial fusion.
Sabouny R et al.·Biochim Biophys Acta Mol Basis Dis
2019
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Mitochondrial DiseasesMitochondrial EncephalomyopathyMitochondrial Encephalopathy

Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome

RECRUITING
NCT04802707Phase PHASE2Kenneth Myers, MDStarted 2021-10-18
deoxycytidine and deoxythymidine

External Resources

Links to major genomics databases and tools