Affinage

ELOVL4

Very long chain fatty acid elongase 4 · UniProt Q9GZR5

Length
314 aa
Mass
36.8 kDa
Annotated
2026-06-09
98 papers in source corpus 39 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ELOVL4 is an endoplasmic reticulum-resident fatty acid elongase that catalyzes the condensation step in the biosynthesis of very long chain fatty acids, generating both very long chain saturated fatty acids (VLC-SFAs, ≥C28) from C24:0–C26:0 precursors and very long chain polyunsaturated fatty acids (VLC-PUFAs, C28–C38) from C20–C22 PUFAs such as EPA, with preferential elongation of 20:5n3 over DHA (PMID:18728184, PMID:22158834). Its catalytic activity depends on conserved active-site histidine residues and on ER localization, but not on N-glycosylation (PMID:24569140); ER retention is enforced by a C-terminal dilysine motif (PMID:15028284). These elongation products serve distinct tissue programs: in skin ELOVL4 is the sole enzyme producing omega-O-acylceramides and ≥C28 free fatty acids required for the epidermal permeability barrier, and its loss causes neonatal-lethal barrier failure rescued by epidermis-specific re-expression (PMID:17208947, PMID:17311087, PMID:21429867); in photoreceptors it supplies VLC-PUFAs enriched in outer-segment phosphatidylcholines (PMID:22199362); in neurons VLC-SFAs in synaptic vesicles set presynaptic neurotransmitter release kinetics and cerebellar synaptic plasticity (PMID:29168048, PMID:34227061); in retinal endothelium VLC-ceramides stabilize tight junctions (PMID:29362226); and in testis VLC-PUFAs are required for spermatogenesis and male fertility (PMID:41495266). ELOVL4 was first identified through a 5-bp deletion causing autosomal dominant Stargardt-like macular dystrophy (STGD3) (PMID:11138005); this and other C-terminal truncations delete the dilysine signal, mislocalize the protein to aggresome-like inclusions, and sequester wild-type ELOVL4, defining a dominant-negative mechanism rather than haploinsufficiency (PMID:15028284, PMID:16036915, PMID:16877435, PMID:17254625, PMID:23509295). By contrast, SCA34-causing missense mutations (e.g., L168F, W246G) selectively impair VLC-SFA but largely spare VLC-PUFA biosynthesis, accounting for their neurological rather than retinal presentation (PMID:32780351, PMID:36464075, PMID:36748939).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2001 High

    Established ELOVL4 as a photoreceptor-expressed gene whose truncation causes a dominant macular dystrophy, linking a putative elongase to inherited retinal disease.

    Evidence Recombination mapping and sequencing of STGD3 families with homology analysis to yeast VLCFA enzymes

    PMID:11138005

    Open questions at the time
    • No direct enzymatic activity demonstrated
    • Substrates and products unknown
  2. 2004 High

    Defined the wild-type ER localization of ELOVL4 via a C-terminal dilysine motif and showed disease truncations mislocalize, framing a localization-based pathology.

    Evidence Immunofluorescence/immuno-EM in human photoreceptors and transfected COS-7/CHO/NIH-3T3/HEK293 cells, organelle markers, TUNEL

    PMID:15028284 PMID:15073583 PMID:15557430

    Open questions at the time
    • Whether mislocalization alone or loss of catalytic product drives disease unresolved
    • No enzymatic activity tested
  3. 2005 High

    Demonstrated a dominant-negative mechanism: truncated ELOVL4 forms aggresomes, binds wild-type protein, recruits it out of the ER, and triggers the UPR.

    Evidence Co-IP, FRET, 2D gel, sucrose gradient, BiP/CHOP Western blot in COS-7/HEK293 cells

    PMID:16036915 PMID:16145543 PMID:16163264

    Open questions at the time
    • Cell-culture overexpression may not reflect photoreceptor context
    • Did not yet quantify loss of catalytic output
  4. 2007 High

    Genetic loss-of-function in mice established ELOVL4 as essential for skin VLC-FA/acylceramide synthesis and proved haploinsufficiency is not the STGD3 mechanism.

    Evidence Knock-in 5-bp deletion and knockout mice, epidermal lipidomics, EM of lamellar bodies, transepidermal water loss, ERG of heterozygotes

    PMID:16877435 PMID:17208947 PMID:17254625 PMID:17304340 PMID:17311087

    Open questions at the time
    • Neonatal lethality precluded study of retinal and neuronal roles
    • Precise C26 substrate-to-product step not directly assayed in vitro
  5. 2008 High

    Provided the first direct biochemical evidence that ELOVL4 is the elongase, defining both VLC-SFA and VLC-PUFA product spectra.

    Evidence Adenoviral gain-of-function expression with labeled FA precursors and FA profiling in cardiomyocytes and ARPE-19 cells

    PMID:18728184

    Open questions at the time
    • Did not resolve which condensation residues are catalytic
    • Substrate preference among PUFAs not yet ranked
  6. 2011 High

    Refined substrate selectivity and defined the photoreceptor lipid product, while excluding ELOVL4 from DHA synthesis.

    Evidence Photoreceptor conditional KO with HPLC-MS lipidomics; ELOVL4 expression with individual substrate supplementation and GC-MS; siRNA in 661W cells

    PMID:20238022 PMID:22158834 PMID:22199362

    Open questions at the time
    • Functional consequence of VLC-PUFA loss in vision not yet dissected from mutant toxicity
  7. 2013 High

    Genetic epistasis separated VLC-PUFA depletion from mutant-protein toxicity, and enzymology confirmed the truncated mutant is catalytically dead and dominant-negative.

    Evidence Rod/cone conditional KO vs STGD3 transgenic mice with ERG/optomotor; cell-free microsome elongase assays with co-expression

    PMID:23479632 PMID:23509295

    Open questions at the time
    • Why VLC-PUFA depletion alone is tolerated in mouse rods left open
    • Identity of the toxic species in transgenic retina unresolved
  8. 2014 High

    Established the catalytic and localization requirements of ELOVL4 and extended its roles to meibomian gland function.

    Evidence Active-site histidine, ER-retention, and glycosylation mutants with elongation assays; immunohistochemistry and ocular phenotyping of Stgd3 mice; in vivo Xenopus rod localization

    PMID:24569140 PMID:24677106 PMID:24833735

    Open questions at the time
    • In vivo Xenopus data did not reproduce wild-type sequestration seen in cell culture
    • Structural basis of substrate selection unknown
  9. 2017 High

    Identified VLC-SFAs as regulators of presynaptic vesicle release, explaining neurological phenotype through synaptic dysfunction.

    Evidence Skin-rescued homozygous STGD3 mice, hippocampal FM1-43 release assay, electrophysiology, VLC-SFA supplementation rescue

    PMID:29168048

    Open questions at the time
    • Molecular target through which VLC-SFAs alter release kinetics unknown
  10. 2018 Medium

    Extended ELOVL4 products to retinal endothelial tight-junction stabilization and germ-cell sphingolipid synthesis.

    Evidence ELOVL4 overexpression/AAV in retinal endothelium with permeability and TJ readouts; radiolabeled arachidonate elongation in isolated testicular germ cells

    PMID:29362226 PMID:29724783

    Open questions at the time
    • Mechanism by which VLC-ceramides stabilize tight junctions not defined
    • Germ-cell findings single-lab, primary-cell based
  11. 2020 High

    Defined the SCA34 mechanism: missense mutations selectively impair VLC-SFA synthesis, accounting for tissue-specific neurological pathology.

    Evidence W246G knock-in rat with GC-MS lipid analysis, ERG, OCT, histology; patient fibroblast localization

    PMID:32211516 PMID:32780351

    Open questions at the time
    • Patient-fibroblast localization is single-method, low-confidence
    • Link between VLC-SFA loss and retinal function decrement not mechanistic
  12. 2021 High

    Demonstrated that ELOVL4 VLC-SFAs are required for cerebellar synaptic plasticity and that ELOVL4 is transcriptionally repressed by MYCN in neuroblastoma.

    Evidence Cerebellar slice LTP/LTD recordings and rotarod in W246G rats; MYCN ChIP at ELOVL4 promoter with siRNA and metabolite/differentiation assays

    PMID:33556440 PMID:34227061 PMID:34333551

    Open questions at the time
    • How VLC-SFAs influence Purkinje synapse plasticity at molecular level unknown
    • Functional consequence of MYCN-driven repression in tumors not fully resolved
  13. 2023 High

    Resolved structural and biochemical basis of SCA34 variant heterogeneity and placed ELOVL4 in an epidermal tumor-suppressor axis and wound-healing program.

    Evidence Cell-based PC elongation assays for multiple variants plus structural modeling and knock-in ES cells; detailed patch-clamp in W246G rats; NOTCH-RIPK4-IRF6/CRISPR tumor models; cooling-induced wound-healing model

    PMID:36464075 PMID:36465696 PMID:36748939 PMID:36765696 PMID:37491316 PMID:37568198 PMID:40083712

    Open questions at the time
    • Direct enzyme structure not solved (modeling only)
    • Mechanism by which ELOVL4 loss permits squamous carcinoma not fully defined
  14. 2026 High

    Established a required role for ELOVL4 VLC-PUFAs in spermatogenesis and male fertility.

    Evidence Testis-specific conditional KO mice with GC-MS lipidomics, sperm phenotyping, and Defbs expression analysis

    PMID:41495266

    Open questions at the time
    • How VLC-PUFA loss alters Defbs expression and sperm motility mechanistically unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular targets through which ELOVL4-derived VLC lipids act on synaptic release machinery, tight junctions, and sperm function remain undefined, and no experimental structure of the enzyme exists.
  • No experimentally determined ELOVL4 structure
  • Lipid-effector interactions at synapses and junctions unmapped
  • Regulation of ELOVL4 expression across tissues incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4
Localization
GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-1430728 Metabolism 3
Partners
ELOVL1ELOVL2ELOVL3ELOVL4ELOVL5ELOVL6ELOVL7

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 ELOVL4 encodes a retinal photoreceptor-specific protein with homology to yeast proteins involved in biosynthesis of very long chain fatty acids; a 5-bp deletion in exon 6 causes protein truncation and is associated with autosomal dominant Stargardt-like macular dystrophy (STGD3). Recombination breakpoint mapping, direct sequencing, bioinformatic homology analysis Nature genetics High 11138005
2004 Wild-type ELOVL4 localizes predominantly to the endoplasmic reticulum (ER) in COS-7 and CHO cells, dependent on a C-terminal dilysine (KXKXX) ER retention/retrieval motif; disease-associated truncation mutants lose ER localization and are redirected to the Golgi compartment. Immunofluorescence with organelle-specific markers, immunoelectron microscopy in human photoreceptors, transfection of COS-7 and CHO cells Genomics High 15028284
2004 Wild-type ELOVL4 localizes to the ER and not to mitochondria, peroxisomes, or Golgi; mutant ELOVL4 (lacking ER retention signal) mislocalizes to cytoplasmic aggregates and induces apoptotic cell death in transfected cells. Confocal microscopy with organelle-specific markers (ER, mitochondria, peroxisomes, Golgi), TUNEL staining, Western blot in NIH-3T3 and HEK293 cells Molecular vision Medium 15073583
2004 A novel Y270X truncation mutation in ELOVL4 causes mislocalization of the mutant protein away from the ER in NIH-3T3 and HEK293 cells, consistent with loss of the ER retention signal. Transfection with EGFP fusion proteins, confocal microscopy with ER marker (pDsRed2-ER), Western blot Investigative ophthalmology & visual science Medium 15557430
2005 Disease-associated C-terminal truncation mutants of ELOVL4 accumulate in aggresome-like juxtanuclear inclusions; wild-type ELOVL4 co-immunoprecipitates with mutant ELOVL4 and is recruited into these aggresomes, establishing a dominant negative mechanism that alters wild-type protein subcellular localization. Immunofluorescence, co-immunoprecipitation, immunoaffinity chromatography in COS-7 and HEK293T cells The Journal of biological chemistry High 16036915
2005 ELOVL4 5-bp deletion mutant interacts with wild-type ELOVL4 and recruits it into perinuclear aggresome-like inclusions; interaction demonstrated by 2D gel electrophoresis and FRET analysis in COS-7 cells. Immunocytochemistry, 2D gel electrophoresis, FRET analysis, Western blot in COS-7 cells Molecular vision Medium 16163264
2005 ELOVL4 truncation mutants cause loss of ER retention and sequestration of wild-type ELOVL4 into non-ER aggregates; mutant expression induces the unfolded protein response (UPR) as evidenced by upregulation of BiP and CHOP. Fluorescence microscopy, co-immunoprecipitation, sucrose gradient centrifugation with immunodetection, Western blot for BiP and CHOP in HEK293 and COS cells Molecular vision Medium 16145543
2007 ELOVL4 is required for synthesis of very long chain fatty acids (≥C28) in skin; homozygous loss-of-function (knock-in 5-bp deletion) in mice depletes C28+ ceramides and free fatty acids, eliminates epidermal omega-O-acylceramides essential for stratum corneum lamellar membranes, and causes lethal epidermal permeability barrier failure. Knock-in mouse model, lipid analysis of epidermis, electron microscopy of lamellar bodies, histopathology, transepidermal water loss measurements Human molecular genetics High 17208947
2007 Homozygous knockout of Elovl4 in mice depletes epidermal ceramides containing omega-hydroxy VLC-FAs (≥C28) and causes accumulation of C26-ceramides, implicating C26 fatty acids as substrates for ELOVL4; skin water permeability barrier failure leads to neonatal death. Elovl4 knockout mice, lipidomic analysis of ceramide fractions, histology of skin, transepidermal water loss International journal of biological sciences High 17311087
2007 Elovl4 knockout mice lacking functional ELOVL4 show a significant reduction in free fatty acids longer than C26 in skin, establishing that ELOVL4 elongates C26 and longer fatty acids in vivo. Elovl4 Y270X mutant and knockout mice, biochemical fatty acid analysis of skin International journal of biological sciences High 17304340
2007 Heterozygous knock-in of the 5-bp deletion in Elovl4 does not cause retinal degeneration, establishing that haploinsufficiency is not the disease mechanism in STGD3; instead, dominant negative effects of mutant protein are required. Heterozygous Elovl4 knockout mice, electroretinography, retinal morphology, Western blot, fatty acid profiling Investigative ophthalmology & visual science High 16877435 17254625
2007 In Stgd3 knock-in mouse retinas, selective deficiency of C32-C36 acyl phosphatidylcholines (but no detectable cellular stress response) was found, indicating that loss of these specific lipid products rather than mutant protein toxicity underlies retinal pathology. Lipid mass spectrometry of knock-in mouse retinas, analysis of cellular stress markers FEBS letters Medium 17983602
2008 ELOVL4 directly catalyzes the elongation of C24:0 to C28:0 and C30:0 saturated fatty acids, and elongates C20:5n3 and C22:5n3 to a series of C28-C38 VLC-PUFAs; this was the first direct experimental evidence for ELOVL4 elongase activity. Gain-of-function adenoviral expression of mouse Elovl4 in rat neonatal cardiomyocytes and ARPE-19 cells, supplementation with labeled FA precursors, fatty acid profiling Proceedings of the National Academy of Sciences of the United States of America High 18728184
2010 ELOVL4 protein does not participate in the biosynthesis of docosahexaenoic acid (DHA, 22:6n3) from shorter-chain precursors (18:3n3 and 22:5n3); siRNA-mediated silencing of ELOVL4 in 661W cone cells did not reduce DHA synthesis. siRNA knockdown of ELOVL4 in 661W cells, fatty acid analysis Advances in experimental medicine and biology Medium 20238022
2011 Photoreceptor-specific conditional knockout of Elovl4 in mice causes significant decrease in retinal glycerophospholipids containing VLC-PUFAs (specifically in the sn-1 position of phosphatidylcholine), abnormal lipid droplet and lipofuscin accumulation, and photoreceptor-specific defects in visual response. Photoreceptor-specific conditional Elovl4 knockout mice, HPLC-MS lipid analysis, immunofluorescence, histology, electroretinography The Journal of biological chemistry High 22199362
2011 ELOVL4 protein preferentially elongates 20:5n3 (EPA) over 20:4n6 and 22:6n3 (DHA) to produce C28-C38 VLC-PUFAs; only ELOVL4-expressing cells synthesize these VLC-PUFAs from C20-C22 PUFA precursors. Expression of ELOVL4 in pheochromocytoma cells, supplementation with individual FA substrates and combinations, GC-MS fatty acid profiling Journal of lipid research Medium 22158834
2013 The STGD3-associated truncated ELOVL4 mutant lacks intrinsic condensation (elongase) activity in cell-based and cell-free microsome assays; co-expression of mutant with wild-type ELOVL4 shows a large dominant negative effect, reducing ELOVL4 localization to ER and enzymatic activity, resulting in reduced VLC-PUFA synthesis. Cell-based and cell-free microsome elongase assays, co-expression studies, VLC-PUFA quantification Proceedings of the National Academy of Sciences of the United States of America High 23509295
2013 Photoreceptor-specific ablation of Elovl4 in rods (conditional KO) depletes retinal VLC-PUFAs by up to 98% but causes no electrophysiological or behavioral deficits, whereas transgenic expression of mutant ELOVL4 (STGD3 allele) causes rod-cone dystrophy despite similar VLC-PUFA depletion; this suggests the mutant protein itself (not simply VLC-PUFA depletion) drives STGD3 pathology. Rod- and cone-specific conditional KO mice vs. STGD3 transgenic mice, GC-MS for VLC-PUFA, electroretinography, optomotor tracking, electron microscopy Proceedings of the National Academy of Sciences of the United States of America High 23479632
2014 ELOVL4 enzymatic activity requires specific conserved histidine residues in its active site (active site histidine mutants lack condensation activity) and requires ER localization (displacing ELOVL4 from ER abolishes activity); N-glycosylation is not required for enzyme function. Active-site histidine mutagenesis, ER-retention mutants, N-glycosylation-deficient mutants expressed in cell culture, fatty acid elongation assays Journal of lipid research High 24569140
2014 In Xenopus laevis transgenic rods, wild-type ELOVL4 localizes to inner segments, while the STGD3 dilysine-deficient mutant is mislocalized to post-Golgi compartments and outer segment disks; co-expression of mutant and wild-type ELOVL4 in rods did NOT result in mislocalization of wild-type protein to outer segments or aggregate formation in vivo. Transgenic Xenopus laevis expressing HA-tagged ELOVL4 variants in rods, immunofluorescence microscopy Investigative ophthalmology & visual science Medium 24833735
2014 ELOVL4 is expressed in meibomian glands and sebaceous glands; Stgd3 mutant mice show meibomian gland abnormalities and increased blink rates resembling evaporative dry eye, establishing a role for ELOVL4-dependent VLC-FAs in meibomian gland function. Immunohistochemistry, hematoxylin-eosin staining, clinical ocular phenotyping of Stgd3 mice Investigative ophthalmology & visual science Medium 24677106
2010 The STGD3 truncated ELOVL4 mutant (ELOVL4ΔC) forms homo-oligomers more strongly than wild-type ELOVL4, and also forms hetero-oligomers with other elongases (ELOVL1-7) more strongly than wild-type; ELOVL4ΔC can form elongase complexes with other components of the VLCFA elongation machinery. Co-immunoprecipitation in HEK293T cells, elongase activity assays for multiple acyl-CoA substrates Molecular vision Medium 21139992
2011 Transgenic expression of ELOVL4 driven by an epidermal-specific involucrin promoter in homozygous Stgd3 mice restores synthesis of epidermal C28-C36 acylceramides and (O-linoleoyl)-omega-hydroxy C28-C36 fatty acids, rescues skin barrier function, and prevents neonatal lethality; establishes that ELOVL4 is the sole enzyme synthesizing these lipids in skin. Skin-specific transgenic rescue of Elovl4 expression in homozygous Stgd3 mice, lipidomic analysis, transepidermal water loss, survival assessment Journal of lipid research High 21429867
2017 Double transgenic mice with homozygous STGD3 Elovl4 mutation (skin-rescued) develop seizures and die by P21; cultured hippocampal neurons from these mice show accelerated synaptic vesicle release kinetics (FM1-43 dye assay), which is rescued by supplementation with VLC-SFAs; establishing that ELOVL4-derived VLC-SFAs regulate presynaptic neurotransmitter release kinetics and epileptogenesis. Skin-specific rescue transgenic + homozygous knock-in mice, hippocampal slice electrophysiology, FM1-43 synaptic vesicle release assay, VLC-SFA supplementation rescue Molecular neurobiology High 29168048
2018 ELOVL4-derived very long chain ceramides (VLC-ceramides, ≥C26) colocalize with tight junction complexes in retinal endothelial cells; ELOVL4 overexpression stabilizes tight junctions and prevents VEGF- and IL-1β-induced permeability; intravitreal AAV2-hELOVL4 delivery reduces diabetes-induced retinal vascular permeability. ELOVL4 overexpression and AAV delivery in cell culture and mouse model, permeability assays, ultrastructural and lipidomic analysis, Western blot for TJ proteins Diabetes High 29362226
2021 VLC-PUFA-containing lipids are enriched in photoreceptor outer segment disks; in neurons, VLC-SFAs are enriched in synaptic vesicles where they regulate the kinetics of presynaptic neurotransmitter release essential for normal neuronal function. Lipid fractionation, mass spectrometry in retina and brain, synaptic vesicle preparations, electrophysiology in VLC-SFA-deficient mice Journal of lipid research Medium 33556440
2020 The W246G ELOVL4 knock-in rat (SCA34 model) shows that the W246G mutation selectively impairs VLC-SFA synthesis but not VLC-PUFA synthesis in retina and skin; homozygous rats show reduced ERG a- and b-wave amplitudes (retinal dysfunction) without photoreceptor degeneration, revealing a role for VLC-SFAs in regulating retinal function independent of neurodegeneration. Knock-in rat model, GC-MS lipid analysis, electroretinography, optical coherence tomography, histology, immunolabeling Molecular neurobiology High 32780351
2021 W246G mutant ELOVL4 rats (SCA34 model) show impaired long-term potentiation at parallel fiber-Purkinje cell synapses and impaired long-term depression at climbing fiber-Purkinje cell synapses, with early motor deficits but no cerebellar neurodegeneration at 6 months; establishing that ELOVL4 VLC-SFAs are required for cerebellar synaptic plasticity. Knock-in rat, cerebellar slice electrophysiology (LTP/LTD recordings), rotarod motor testing, neuroanatomical analysis Molecular neurobiology High 34227061
2022 SCA34-causing ELOVL4 mutations L168F and W246G are deficient in VLC-SFA biosynthesis (especially W246G, which shows negligible VLC-SFA synthesis) but retain VLC-PUFA biosynthetic capability; L168F shows a gain-of-function producing 38:5n3 not made by WT; this differential loss of VLC-SFA vs. VLC-PUFA production may explain tissue-specific pathology (brain/skin but not retina) in SCA34. Expression of WT and mutant ELOVL4 in cell culture, supplementation with VLC-PUFA and VLC-SFA precursors, GC-MS quantification of FA methyl esters Journal of lipid research High 36464075
2023 Five SCA34-causing ELOVL4 mutants produce shorter ultra-long-chain (ULC) polyunsaturated FA-containing phosphatidylcholines than wild-type; structural modeling places substituted residues in transmembrane helices interacting with the ω-end region of the substrate acyl-CoA, explaining incomplete elongation; heterozygous Q180P and homozygous W246G mouse embryonic stem cells show neuronal differentiation-dependent reduction of ULC-PCs. Cell-based phosphatidylcholine elongation assay for 5 SCA34 mutants, knock-in mouse embryonic stem cells, neuronal differentiation, lipidomics, structural modeling Molecular and cellular biology High 36748939
2023 In W246G ELOVL4 mutant rat cerebellum, miniature EPSC frequency (but not amplitude) is reduced at Purkinje cell synapses, indicating a presynaptic defect in excitatory transmission; miniature IPSC frequency and amplitude are increased; paired-pulse ratio changes suggest opposite effects on release probability at parallel fiber vs. climbing fiber synapses; dendritic spine density is reduced in Purkinje cells. Patch-clamp electrophysiology (mEPSC, mIPSC recordings), paired-pulse ratio, high-frequency stimulation, dendritic spine morphometry in SCA34 knock-in rats The Journal of neuroscience High 37491316
2023 Elovl4 is a downstream target of the NOTCH-RIPK4-IRF6 tumor suppressor axis in epidermis; loss of Elovl4 in skin triggers squamous cell carcinoma development, and overexpression of Elovl4 suppresses tumor growth in Ripk4-deficient keratinocytes. Autochthonous mouse tumor models (Pik3caH1047R oncogene), in vivo CRISPR screening, Elovl4 loss-of-function and overexpression rescue experiments in keratinocytes Cancers High 36765696
2018 In rat spermatocytes, ELOVL4 protein is a germ cell-specific product (absent from Sertoli cells), displays the highest protein levels and elongase activity in spermatocytes, and is responsible for elongation of arachidonate to C26-C32 polyunsaturated FAs present in germ cell sphingolipids. Immunohistochemistry, Western blot, [3H]arachidonate radiolabeled elongation assay in isolated germ cell populations and Sertoli cells Journal of lipid research Medium 29724783
2023 A novel L168S ELOVL4 variant is deficient in both VLC-SFA and VLC-PUFA biosynthesis in cell culture, differentiating it from L168F (which retains VLC-PUFA synthesis) and suggesting combined VLC-SFA and VLC-PUFA deficiency underlies early-childhood SCA34 with retinal dysfunction. Expression of L168S ELOVL4 variant in cell culture, supplementation with VLC-PUFA and VLC-SFA precursors, GC-MS fatty acid profiling Acta neuropathologica communications Medium 37568198
2020 SCA34 patient-derived fibroblasts show mislocalization of ELOVL4 protein appearing punctate and aggregated (not in normal ER distribution), supporting dominant negative effect of the L168F mutation on protein localization in human cells. Immunohistochemistry of patient-derived dermal fibroblasts Neurology. Genetics Low 32211516
2021 MYCN binds to the ELOVL4 promoter in proximity to HDAC1, HDAC2, and Sp1 to transcriptionally repress ELOVL4 expression; ELOVL4 positively regulates neuronal differentiation and lipid droplet accumulation in neuroblastoma cells; MYCN silencing increases FA34:6 production. ChIP for MYCN at ELOVL4 promoter, MYCN siRNA knockdown with FA34:6 metabolite measurement, neuronal differentiation assays in neuroblastoma cells Oncogene Medium 34333551
2025 Contact cooling of wounded skin to 20°C induces ELOVL4 expression in injured epidermis; ELOVL4-derived DHA and EPA dampen TNFα and other pro-inflammatory cytokine expression, promoting the transition from inflammation to the proliferation phase of wound healing. Skin injury model, skin organoids, bulk/single-cell RNA-seq, spatial transcriptomics, in vivo ELOVL4 perturbation, cytokine measurement, wound healing rate quantification International journal of biological sciences Medium 40083712
2026 Testis-specific knockout of Elovl4 (Stra8-Cre) abolishes VLC-PUFA (>C26) synthesis in testes, causes abnormal spermatogenesis, reduced sperm count, sperm malformation, markedly decreased sperm motility with altered Defbs gene family expression, and reduced male fertility. Testis-specific Elovl4 conditional KO mice, lipid analysis by GC-MS, sperm motility and morphology assessment, RT-PCR/qPCR/Western blot/immunohistochemistry for Defbs expression Scientific reports High 41495266

Source papers

Stage 0 corpus · 98 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nature genetics 365 11138005
2008 Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids. Proceedings of the National Academy of Sciences of the United States of America 224 18728184
2007 Loss of functional ELOVL4 depletes very long-chain fatty acids (> or =C28) and the unique omega-O-acylceramides in skin leading to neonatal death. Human molecular genetics 214 17208947
2011 Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia. American journal of human genetics 156 22100072
2005 Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: a model for macular degeneration. Proceedings of the National Academy of Sciences of the United States of America 152 15749821
2007 Depletion of ceramides with very long chain fatty acids causes defective skin permeability barrier function, and neonatal lethality in ELOVL4 deficient mice. International journal of biological sciences 135 17311087
2001 Diverse macular dystrophy phenotype caused by a novel complex mutation in the ELOVL4 gene. Investigative ophthalmology & visual science 134 11726641
2010 Retinal very long-chain PUFAs: new insights from studies on ELOVL4 protein. Journal of lipid research 132 20299492
2007 Essential role of Elovl4 in very long chain fatty acid synthesis, skin permeability barrier function, and neonatal survival. International journal of biological sciences 121 17304340
2009 Remodeling of retinal Fatty acids in an animal model of diabetes: a decrease in long-chain polyunsaturated fatty acids is associated with a decrease in fatty acid elongases Elovl2 and Elovl4. Diabetes 114 19875612
2014 Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia. JAMA neurology 100 24566826
2019 Novel Cellular Functions of Very Long Chain-Fatty Acids: Insight From ELOVL4 Mutations. Frontiers in cellular neuroscience 90 31616255
2010 Expression and role of Elovl4 elongases in biosynthesis of very long-chain fatty acids during zebrafish Danio rerio early embryonic development. Biochimica et biophysica acta 82 20601113
2004 Characterization of mouse orthologue of ELOVL4: genomic organization and spatial and temporal expression. Genomics 79 15028285
2004 A novel mutation in the ELOVL4 gene causes autosomal dominant Stargardt-like macular dystrophy. Investigative ophthalmology & visual science 78 15557430
2011 Essential role of ELOVL4 protein in very long chain fatty acid synthesis and retinal function. The Journal of biological chemistry 77 22199362
2005 Dominant negative mechanism underlies autosomal dominant Stargardt-like macular dystrophy linked to mutations in ELOVL4. The Journal of biological chemistry 75 16036915
2015 A Novel Mutation in ELOVL4 Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia: A Broadened Spectrum of SCA34. JAMA neurology 70 26010696
2018 ELOVL4: Very long-chain fatty acids serve an eclectic role in mammalian health and function. Progress in retinal and eye research 69 30982505
2011 Biosynthesis of very long-chain fatty acids (C>24) in Atlantic salmon: cloning, functional characterisation, and tissue distribution of an Elovl4 elongase. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 64 21377536
2021 Very long chain fatty acid-containing lipids: a decade of novel insights from the study of ELOVL4. Journal of lipid research 62 33556440
2019 Taxonomy and Broad-Spectrum Antifungal Activity of Streptomyces sp. SCA3-4 Isolated From Rhizosphere Soil of Opuntia stricta. Frontiers in microbiology 58 31316480
2007 A Stargardt disease-3 mutation in the mouse Elovl4 gene causes retinal deficiency of C32-C36 acyl phosphatidylcholines. FEBS letters 57 17983602
2011 ELOVL4 protein preferentially elongates 20:5n3 to very long chain PUFAs over 20:4n6 and 22:6n3. Journal of lipid research 55 22158834
2005 Loss of ER retention and sequestration of the wild-type ELOVL4 by Stargardt disease dominant negative mutants. Molecular vision 55 16145543
2005 Stargardt-like macular dystrophy protein ELOVL4 exerts a dominant negative effect by recruiting wild-type protein into aggresomes. Molecular vision 54 16163264
2006 Elovl4 5-bp-deletion knock-in mice develop progressive photoreceptor degeneration. Investigative ophthalmology & visual science 53 17003453
2004 Atrophic macular degeneration mutations in ELOVL4 result in the intracellular misrouting of the protein. Genomics 52 15028284
2013 Role of ELOVL4 and very long-chain polyunsaturated fatty acids in mouse models of Stargardt type 3 retinal degeneration. Proceedings of the National Academy of Sciences of the United States of America 48 23479632
2011 Production of ELOVL4 transgenic pigs: a large animal model for Stargardt-like macular degeneration. The British journal of ophthalmology 48 21873315
2018 Stargardt Phenotype Associated With Two ELOVL4 Promoter Variants and ELOVL4 Downregulation: New Possible Perspective to Etiopathogenesis? Investigative ophthalmology & visual science 46 29417145
2014 A role for ELOVL4 in the mouse meibomian gland and sebocyte cell biology. Investigative ophthalmology & visual science 46 24677106
2015 Polyunsaturated fatty acid metabolism in a marine teleost, Nibe croaker Nibea mitsukurii: Functional characterization of Fads2 desaturase and Elovl5 and Elovl4 elongases. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 43 26112824
2018 ELOVL4-Mediated Production of Very Long-Chain Ceramides Stabilizes Tight Junctions and Prevents Diabetes-Induced Retinal Vascular Permeability. Diabetes 41 29362226
2013 Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy. Proceedings of the National Academy of Sciences of the United States of America 40 23509295
2006 Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease. Investigative ophthalmology & visual science 40 16877435
2003 Elovl4 mRNA distribution in the developing mouse retina and phylogenetic conservation of Elovl4 genes. Molecular vision 39 12847421
2017 Homozygous Expression of Mutant ELOVL4 Leads to Seizures and Death in a Novel Animal Model of Very Long-Chain Fatty Acid Deficiency. Molecular neurobiology 37 29168048
2009 Elovl4 5-bp deletion knock-in mouse model for Stargardt-like macular degeneration demonstrates accumulation of ELOVL4 and lipofuscin. Experimental eye research 37 19682985
2004 Expression of wild type and mutant ELOVL4 in cell culture: subcellular localization and cell viability. Molecular vision 36 15073583
2001 Evaluation of the ELOVL4 gene in patients with age-related macular degeneration. Ophthalmic genetics 35 11803489
2009 DHA does not protect ELOVL4 transgenic mice from retinal degeneration. Molecular vision 33 19536303
2006 Association of adipose and red blood cell lipids with severity of dominant Stargardt macular dystrophy (STGD3) secondary to an ELOVL4 mutation. Archives of ophthalmology (Chicago, Ill. : 1960) 32 16476896
2019 A family with spinocerebellar ataxia and retinitis pigmentosa attributed to an ELOVL4 mutation. Neurology. Genetics 31 31750392
2011 Epidermal expression of an Elovl4 transgene rescues neonatal lethality of homozygous Stargardt disease-3 mice. Journal of lipid research 31 21429867
2017 Distribution of ELOVL4 in the Developing and Adult Mouse Brain. Frontiers in neuroanatomy 30 28507511
2014 A novel recessive mutation in the gene ELOVL4 causes a neuro-ichthyotic disorder with variable expressivity. BMC medical genetics 30 24571530
2020 Characterization of the phenotype with cognitive impairment and protein mislocalization in SCA34. Neurology. Genetics 27 32211516
2007 Elovl4 haploinsufficiency does not induce early onset retinal degeneration in mice. Vision research 26 17254625
2016 Different Mutations in ELOVL4 Affect Very Long Chain Fatty Acid Biosynthesis to Cause Variable Neurological Disorders in Humans. Advances in experimental medicine and biology 25 26427403
2017 Molecular and functional characterisation of two elovl4 elongases involved in the biosynthesis of very long-chain (>C24) polyunsaturated fatty acids in black seabream Acanthopagrus schlegelii. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 24 28668330
2014 Endoplasmic reticulum microenvironment and conserved histidines govern ELOVL4 fatty acid elongase activity. Journal of lipid research 24 24569140
2010 Hetero-oligomeric interactions of an ELOVL4 mutant protein: implications in the molecular mechanism of Stargardt-3 macular dystrophy. Molecular vision 24 21139992
2021 Increased VLCFA-lipids and ELOVL4 underlie neurodegeneration in frontotemporal dementia. Scientific reports 20 34725421
2014 Mutant ELOVL4 that causes autosomal dominant stargardt-3 macular dystrophy is misrouted to rod outer segment disks. Investigative ophthalmology & visual science 19 24833735
2012 Evaluation of the ELOVL4, PRPH2 and ABCA4 genes in patients with Stargardt macular degeneration. Molecular medicine reports 19 22948568
2022 ELOVL4 Mutations That Cause Spinocerebellar Ataxia-34 Differentially Alter Very Long Chain Fatty Acid Biosynthesis. Journal of lipid research 18 36464075
2018 Elovl4 and Fa2h expression during rat spermatogenesis: a link to the very-long-chain PUFAs typical of germ cell sphingolipids. Journal of lipid research 18 29724783
2021 The expression of ELOVL4, repressed by MYCN, defines neuroblastoma patients with good outcome. Oncogene 17 34333551
2020 Two Elongases, Elovl4 and Elovl6, Fulfill the Elongation Routes of the LC-PUFA Biosynthesis Pathway in the Orange Mud Crab (Scylla olivacea). Journal of agricultural and food chemistry 17 32186869
2020 The Elovl4 Spinocerebellar Ataxia-34 Mutation 736T>G (p.W246G) Impairs Retinal Function in the Absence of Photoreceptor Degeneration. Molecular neurobiology 17 32780351
2023 The NOTCH-RIPK4-IRF6-ELOVL4 Axis Suppresses Squamous Cell Carcinoma. Cancers 16 36765696
2021 W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34. Molecular neurobiology 16 34227061
2019 Molecular and functional characterisation of a putative elovl4 gene and its expression in response to dietary fatty acid profile in Atlantic bluefin tuna (Thunnus thynnus). Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 16 31669375
2018 Long-term follow-up of autosomal dominant Stargardt macular dystrophy (STGD3) subjects enrolled in a fish oil supplement interventional trial. Ophthalmic genetics 16 29377748
2017 Elongation of very Long-Chain (>C24) Fatty Acids in Clarias gariepinus: Cloning, Functional Characterization and Tissue Expression of elovl4 Elongases. Lipids 16 28856549
2017 Cloning, tissue distribution and nutritional regulation of a fatty acyl Elovl4-like elongase in mud crab, Scylla paramamosain (Estampador, 1949). Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 16 29277642
2017 Elovl4 can effectively elongate C18 polyunsaturated fatty acids in loach Misgurnus anguillicaudatus. Biochemical and biophysical research communications 16 29287723
2018 Photoreceptor-induced RPE phagolysosomal maturation defects in Stargardt-like Maculopathy (STGD3). Scientific reports 15 29654292
2014 Dominant Stargardt Macular Dystrophy (STGD3) and ELOVL4. Advances in experimental medicine and biology 15 24664730
2009 Inner retina remodeling in a mouse model of stargardt-like macular dystrophy (STGD3). Investigative ophthalmology & visual science 15 19933199
2015 Early Onset Ultrastructural and Functional Defects in RPE and Photoreceptors of a Stargardt-Like Macular Dystrophy (STGD3) Transgenic Mouse Model. Investigative ophthalmology & visual science 14 26529045
2014 Long-term retinal cone survival and delayed alteration of the cone mosaic in a transgenic mouse model of stargardt-like dystrophy (STGD3). Investigative ophthalmology & visual science 14 24334447
2010 Role of Elovl4 protein in the biosynthesis of docosahexaenoic acid. Advances in experimental medicine and biology 14 20238022
2003 Molecular cloning of ELOVL4 gene from cynomolgus monkey (Macaca fascicularis). Experimental animals 14 12806887
2020 Cloning and functional characterization of an elovl4-like gene involved in the biosynthesis of long-chain polyunsaturated fatty acids in the swimming crab Portunus trituberculatus. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 13 31958500
2020 Molecular and Functional Characterization of Elovl4 Genes in Sparus aurata and Solea senegalensis Pointing to a Critical Role in Very Long-Chain (>C24) Fatty Acid Synthesis during Early Neural Development of Fish. International journal of molecular sciences 13 32429178
2023 Synapse-Specific Defects in Synaptic Transmission in the Cerebellum of W246G Mutant ELOVL4 Rats-a Model of Human SCA34. The Journal of neuroscience : the official journal of the Society for Neuroscience 11 37491316
2021 Two Italian Patients with ELOVL4-Related Neuro-Ichthyosis:  Expanding the Genotypic and Phenotypic Spectrum and Ultrastructural Characterization. Genes 11 33652762
2021 Neuropathology of SCA34 showing widespread oligodendroglial pathology with vacuolar white matter degeneration: a case study. Acta neuropathologica communications 10 34689836
2014 In vivo effect of mutant ELOVL4 on the expression and function of wild-type ELOVL4. Investigative ophthalmology & visual science 10 24644051
2003 Evaluation of the ELOVL4 gene in patients with autosomal recessive retinitis pigmentosa and Leber congenital amaurosis. Molecular vision 9 12592226
2014 Biosynthesis of very long-chain polyunsaturated fatty acids in hepatocytes expressing ELOVL4. Advances in experimental medicine and biology 8 24664752
2023 SCA34 caused by ELOVL4 L168F mutation is a lysosomal lipid storage disease sharing pathology features with neuronal ceroid lipofuscinosis and peroxisomal disorders. Acta neuropathologica 7 37184663
2023 A novel ELOVL4 variant, L168S, causes early childhood-onset Spinocerebellar ataxia-34 and retinal dysfunction: a case report. Acta neuropathologica communications 7 37568198
2018 Elovl4 5-bp deletion does not accelerate cone photoreceptor degeneration in an all-cone mouse. PloS one 7 29293603
2023 Incomplete Elongation of Ultra-long-chain Polyunsaturated Acyl-CoAs by the Fatty Acid Elongase ELOVL4 in Spinocerebellar Ataxia Type 34. Molecular and cellular biology 6 36748939
2023 Expanding the allelic spectrum of ELOVL4-related autosomal recessive neuro-ichthyosis. Molecular genetics & genomic medicine 6 37592902
2003 Autosomal dominant Stargardt-like macular dystrophy: identification of a new family with a mutation in the ELOVL4 gene. American journal of ophthalmology 5 12967813
2005 Evaluation of the ELOVL4 gene in a Chinese family with autosomal dominant STGD3-like macular dystrophy. Journal of cellular and molecular medicine 4 16364203
2025 Contact Cooling-Induced ELOVL4 Enhances Skin Wound Healing by Promoting the Inflammation-to-Proliferation Phase Transition. International journal of biological sciences 3 40083712
2024 The Spinocerebellar Ataxia 34-Causing W246G ELOVL4 Mutation Does Not Alter Cerebellar Neuron Populations in a Rat Model. Cerebellum (London, England) 1 38850484
2022 [Construction of a testis Elovl4 gene knockout mouse model based on Cre/loxP system]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 1 36002420
2010 [Association of M299V variant in ELOVL4 gene with exudative age-related macular degeneration in a Chinese population]. [Zhonghua yan ke za zhi] Chinese journal of ophthalmology 1 20388345
2026 Testis-specific knockout of Elovl4 reduces sperm motility and fertility in male mice. Scientific reports 0 41495266
2025 Correlation and regression analysis of the KRT27 and ELOVL4 genes in cashmere fineness and other production performances in Liaoning cashmere goats. Archives animal breeding 0 42256737
2023 Acral collodion membrane associated with ichthyosis due to a heterozygous pathogenic variant of ELOVL4 gene. Pediatric dermatology 0 36623811
2020 Functional characterization, tissue distribution and nutritional regulation of the Elovl4 gene in golden pompano, Trachinotus ovatus (Linnaeus, 1758). Gene 0 32916248

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