Alternative titles; symbols
HGNC Approved Gene Symbol: CYP4F3
Cytogenetic location: 19p13.12 Genomic coordinates (GRCh38): 19:15,640,897-15,662,825 (from NCBI)
The CYP4F3 gene encodes an omega hydroxylase that oxidizes the inflammatory marker leukotriene B4 (LTB4), prostaglandins, and fatty acid epoxides (summary by Smeets et al., 2022).
Leukotrienes are a group of bioactive compounds that play important roles in such processes as inflammation. Kikuta et al. (1993) isolated a cDNA for human leukotriene B4 omega-hydroxylase (LTB4H), an enzyme that catalyzes the omega-hydroxylation of leukotriene B4. The deduced 520-amino acid LTB4H protein has a predicted molecular mass of 59,805 Da. It contains a cysteine in the conserved heme-binding domain near the C-terminus, which is a characteristic feature of the cytochrome P450 superfamily; the protein shares 31 to 44% similarity with CYP4A, CYP4B (124075), and CYP4C. Kikuta et al. (1993) detected transcript from the LTB4H gene in polymorphonuclear leukocytes and leukocytes.
The CYP4F3 gene undergoes tissue-specific alternative splicing generating CYP4F3A, predominantly expressed in neutrophils, and CYP4F3B, expressed in liver and kidney. They differ by incorporation of exon 4 or exon 3, respectively (summary by Smeets et al., 2022).
Kikuta et al. (1998) determined that the CYP4F3 gene contains 13 exons and spans approximately 22.2 kb.
By fluorescence in situ hybridization, Kikuta et al. (1998) mapped the CYP4F3 gene to chromosome 19p13.2.
The CYP4F3A isoform has a high affinity for proinflammatory LTB4. CYP4F3A, like all cytochrome P450 enzymes, requires cofactor NADPH as an electron source and also needs electron transfer partners for its enzymatic oxidase activity (summary by Smeets et al., 2022).
Associations Pending Confirmation
For discussion of a possible association between variation in the CYP4F3 gene and a complex immune phenotype characterized by muscle weakness, exhaustion, and inflammatory-related conditions, see 601270.0001.
This variant is classified as a variant of unknown significance because its contribution to a complex immune phenotype characterized by muscle weakness, exhaustion, and inflammatory-related conditions has not been confirmed.
In a 26-year-old woman with a complex immune phenotype characterized by muscle weakness, exhaustion, and inflammatory-related conditions, Smeets et al. (2022) identified a de novo heterozygous c.1123C-G transversion (c.1123C-G, NM_000896.3) in exon 10 of the CYP4F3 gene, resulting in a leu375-to-val (L375V) substitution at a conserved residue. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP database. Hamosh (2023) noted that the L375V variant was present in 1 of 251,274 alleles in gnomAD, for an allele frequency of 3.98 x 10(-6) (February 23, 2023). In vitro functional expression studies in transfected HEK293 cells showed that the variant decreased CYP4F3 catalytic activity by about 50%, leading to reduced metabolism of the proinflammatory marker LTB4, which was significantly increased in the patient's plasma compared to controls. Although the variant did not affect binding to electron carriers, molecular modeling suggested that the L375V variant may destabilize residues involved in electron transfer between CYP4F3 and electron carriers; this would disrupt catalytic activity. The patient developed severe asthma at 7 years of age. She was treated with high-dose fluticasone that was associated with adrenocortical insufficiency and corticosteroid myopathy causing her to use a wheelchair for mobility. Although asthma resolved around age 14, she later developed gastritis, chronic fatigue syndrome, joint pain, and persistent exhaustion. The disorder was progressive, and she was noted to have accelerated aging, as well as multiple inflammatory conditions, including lateral epicondylitis, paronychia, irritable bowel syndrome, arthritis, infectious enteritis, herpangina, and vestibular neuritis. Immunophenotyping of patient leukocytes showed increased total naive B cells and decreased total switched memory B cells compared to controls. Naive CD4+ and CD8+ T cells were also mildly increased. In vitro studies of whole blood derived from the patient showed that treatment with zileuton, an orally active 5-lipoxygenase (5-LO) inhibitor, abolished LTB4 production, suggesting a possible therapeutic avenue.
Hamosh, A. Personal Communication. Baltimore, Md. 02/23/2023.
Kikuta, Y., Kato, M., Yamashita, Y., Miyauchi, Y., Tanaka, K., Kamada, N., Kusunose, M. Human leukotriene B4 omega-hydroxylase (CYP4F3) gene: molecular cloning and chromosomal localization. DNA Cell Biol. 17: 221-230, 1998. [PubMed: 9539102] [Full Text: https://doi.org/10.1089/dna.1998.17.221]
Kikuta, Y., Kusunose, E., Endo, K., Yamamoto, S., Sogawa, K., Fujii-Kuriyama, Y., Kusunose, M. A novel form of cytochrome P-450 family 4 in human polymorphonuclear leukocytes: cDNA cloning and expression of leukotriene B4 omega-hydroxylase. J. Biol. Chem. 268: 9376-9380, 1993. [PubMed: 8486631]
Smeets, E., Huang, S., Lee, X. Y., Van Nieuwenhove, E., Helsen, C., Handle, F., Moris, L., El Kharraz, S., Eerlings, R., Devlies, W., Willemsen, M., Bucken, L., Prezzemolo, T., Humblet-Baron, S., Voet, A., Rochtus, A., Van Schepdael, A., de Zegher, F., Claessens, F. A disease-associated missense mutation in CYP4F3 affects the metabolism of leukotriene B4 via disruption of electron transfer. J. Cachexia Sarcopenia Muscle 13: 2242-2253, 2022. [PubMed: 35686338] [Full Text: https://doi.org/10.1002/jcsm.13022]