F-Box and Leucine-Rich Repeat Protein 4

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OMIM Number

605654

NCBI Gene ID

26235

Uniprot ID

Q9UKA2

Length

79,472 bases

No. of Exons

12

No. of isoforms

1

Protein Name

F-box/LRR-repeat protein 3

Molecular Mass

70097 Da

Amino Acid Count

621

Genomic Location

chr6:98,868,535-98,948,006

Gene Map Locus
6q16.1-q16.2

Description

The FBXL4 gene encodes F-Box and Leucine-Rich Repeat Protein 4, a protein localized to the mitochondrial intermembrane space.  As the name suggests, the protein contains an F box at its N-terminal, followed by 11 leucine rich repeats.  The F-box is an approximately 40 amino acid motif that is involved in the mediation of protein-protein interactions and binds directly to S-phase kinase-associated protein 1 (SKP1).  Members of the F-box family of proteins constitute one component of the modular E3 ubiquitin protein ligases.  These complexes are also known as SCFs (SKP1, cullin, F-box proteins) and function in phosphorylation dependent ubiquitination.

Defects in FBXL4 are associated with Mitochondrial DNA Depletion Syndrome 13 (Encephalomyopathic Type), (MTDPS13), an often fatal, infantile-onset disorder.  It is caused by defects in mitochondrial oxidative phosphorylation and decreased mtDNA content.  The disease is characterized by encephalopathy, severe global developmental delay, cerebral atrophy, white matter abnormalities, facial dysmorphia, hypotonia and lactic acidosis.  Expression of wildtype FBXL4 in the cells of individuals affected by MTDPS13 results in the rescue of mitochondrial biochemical defects and mtDNA depletion. 

Molecular Genetics

The FBXL4 gene is located on the long arm of chromosome 6.  It spans a length of 79.4 kb of DNA and its coding sequence is spread across 12 exons.  The protein product encoded by this gene has a molecular mass of 70 kDa and consists of 621 amino acids.  The gene has been found to be expressed in the heart, kidney, liver, lung, pancreas and placenta.  Homozygous mutations in the FBXL4 gene are associated with MTDPS13.  So far about five different variants have been identified in the gene, resulting in amino acid substitutions or premature truncation.

Epidemiology in the Arab World

View Map
Variant NameCountryGenomic LocationClinvar Clinical SignificanceCTGA Clinical Significance Condition(s)HGVS ExpressionsdbSNPClinvar
NM_001278716.2:c.1444C>TSaudi ArabiaNC_000006.12:g.98875673G>ALikely Pathogenic, PathogenicLikely PathogenicMitochondrial DNA Depletion Syndrome 13 (Encephalomyopathic Type)NG_033903.2:g.77273C>T; NM_001278716.2:c.1444C>T; NP_001265645.1:p.Arg482Trp39812306166093
NM_001278716.2:c.1703G>CSaudi ArabiaNC_000006.12:g.98874441C>GLikely Pathogenic, PathogenicLikely PathogenicMitochondrial DNA Depletion Syndrome 13 (Encephalomyopathic Type)NG_033903.2:g.78505G>C; NM_001278716.2:c.1703G>C; NP_001265645.1:p.Gly568Ala39812306066092
NM_012160.4:c.1067delUnited Arab EmiratesNC_000006.12:g.98905463delPathogenicPathogenicMitochondrial DNA Depletion Syndrome 13 (Encephalomyopathic Type)NG_033903.1:g.47545del; NM_012160.4:c.1067del; NP_036292.2:p.Gly356AlafsTer151554219474437498
NM_012160.4:c.1303C>TLebanonchr6:98899282PathogenicPathogenicMitochondrial DNA Depletion Syndrome 13 (Encephalomyopathic Type)NG_033903.1:g.53725C>T; NM_012160.4:c.1303C>T; NP_036292.2:p.Arg435Ter20188929466091
NM_012160.4:c.1304G>TUnited Arab EmiratesNC_000006.12:g.98899281C>ALikely PathogenicLikely Pathogenic, PathogenicMitochondrial DNA Depletion Syndrome 13 (Encephalomyopathic Type)NG_033903.1:g.53726G>T; NM_012160.4:c.1304G>T; NP_036292.2:p.Arg435Leu754142863437476
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