Affinage

ELOVL4

Very long chain fatty acid elongase 4 · UniProt Q9GZR5

Length
314 aa
Mass
36.8 kDa
Annotated
2026-04-28
97 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ELOVL4 is an endoplasmic reticulum-resident fatty acid condensing enzyme (elongase) that uniquely catalyzes the synthesis of very long-chain saturated fatty acids (VLC-SFA, ≥C28) and very long-chain polyunsaturated fatty acids (VLC-PUFA, C28–C38) from C26 and shorter acyl-CoA precursors, with activity dependent on conserved active-site histidine residues and ER localization maintained by a C-terminal dilysine retrieval motif (PMID:18728184, PMID:24569140, PMID:15028284). Its lipid products serve tissue-specific structural and signaling roles: omega-O-acylceramides are essential for the epidermal permeability barrier (PMID:17208947, PMID:21429867), VLC-PUFA-containing phosphatidylcholines support photoreceptor membrane integrity (PMID:22199362), VLC-ceramides stabilize retinal vascular tight junctions (PMID:29362226), VLC-SFAs regulate synaptic vesicle release kinetics and cerebellar synaptic plasticity (PMID:29168048, PMID:34227061), and testicular VLC-PUFAs are required for normal spermatogenesis and male fertility (PMID:41495266). Dominant mutations causing autosomal dominant Stargardt-like macular dystrophy (STGD3) truncate the C-terminus, abolish elongase activity, and exert a dominant-negative effect by sequestering wild-type ELOVL4 into aggresomes, while distinct missense mutations causing spinocerebellar ataxia type 34 (SCA34) selectively impair VLC-SFA synthesis and produce incompletely elongated acyl chains, leading to synaptic dysfunction without acute neurodegeneration (PMID:23509295, PMID:16036915, PMID:36464075, PMID:36748939).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2001 High

    Identification of ELOVL4 as the STGD3 disease gene established that a photoreceptor-expressed protein with homology to yeast fatty acid elongases underlies autosomal dominant Stargardt-like macular dystrophy via a 5-bp deletion causing C-terminal truncation.

    Evidence Genetic mapping, recombination breakpoint analysis, direct sequencing, and bioinformatic homology in STGD3 families

    PMID:11138005

    Open questions at the time
    • Enzymatic activity was not directly demonstrated
    • Mechanism of pathogenesis (loss-of-function vs. toxic gain-of-function) was unknown
  2. 2004 High

    Localization studies revealed that wild-type ELOVL4 resides in the ER via a C-terminal dilysine (KXKXX) retrieval motif, and that disease-causing truncations ablate this signal, causing mislocalization to aggregates or the Golgi, directly implicating ER residency in normal function.

    Evidence Immunofluorescence with organelle markers, immunoelectron microscopy in transfected COS-7, CHO, NIH-3T3, HEK293 cells and human photoreceptors

    PMID:15028284 PMID:15073583 PMID:15557430

    Open questions at the time
    • Whether mislocalization per se or loss of enzymatic activity drives pathology was unresolved
    • The ER microenvironment requirement for catalysis had not been tested
  3. 2005 High

    The dominant-negative mechanism of STGD3 was established: truncated ELOVL4 physically interacts with and sequesters wild-type ELOVL4 into aggresome-like inclusions, forming higher-order oligomeric complexes and inducing the unfolded protein response.

    Evidence Co-immunoprecipitation, FRET, 2D gel electrophoresis, UPR marker analysis in COS-7 and HEK293T cells

    PMID:16036915 PMID:16145543 PMID:16163264

    Open questions at the time
    • Whether WT sequestration occurs in photoreceptors in vivo was uncertain
    • Enzymatic activity of WT vs. mutant had not been measured directly
  4. 2007 High

    Knockout and knock-in mouse models proved that ELOVL4 is the sole enzyme responsible for synthesizing ≥C28 fatty acids in skin, and that loss of these VLC-FAs (particularly omega-O-acylceramides) collapses the epidermal permeability barrier, causing neonatal lethality.

    Evidence Elovl4 knockout and Stgd3 knock-in mice with lipid profiling, electron microscopy, and transepidermal water loss assays

    PMID:17208947 PMID:17304340 PMID:17311087

    Open questions at the time
    • Brain and retinal phenotypes could not be assessed due to neonatal death
    • VLC-PUFA vs. VLC-SFA contributions were not separated
  5. 2007 Medium

    Lipidomic analysis of STGD3 knock-in retinas revealed selective depletion of C32–C36 acyl phosphatidylcholines without ER stress markers, suggesting product deficiency rather than ER stress as the primary retinal pathogenic mechanism.

    Evidence Mass spectrometry lipid profiling and ER stress marker analysis of Stgd3 knock-in mouse retinas

    PMID:17983602

    Open questions at the time
    • Heterozygous model may not fully recapitulate disease severity
    • Protein toxicity vs. lipid loss was not definitively resolved
  6. 2008 High

    Direct enzymatic characterization proved that ELOVL4 is a fatty acid condensing enzyme that elongates C24:0 to C28–C30 saturated species and C20–C22 PUFAs to C28–C38 VLC-PUFAs, definitively establishing its biochemical function.

    Evidence Adenoviral Elovl4 expression in cardiomyocytes and ARPE-19 cells with fatty acid supplementation and GC-MS quantification

    PMID:18728184

    Open questions at the time
    • Substrate specificity across different PUFA series was incompletely defined
    • Whether activity required ER localization was untested
  7. 2011 High

    Photoreceptor-specific conditional knockout demonstrated that ELOVL4 is essential for retinal VLC-PUFA-containing phosphatidylcholine synthesis and normal visual function, while epidermal transgenic rescue of neonatal lethality enabled study of tissue-specific roles.

    Evidence Cre-lox photoreceptor-specific KO with HPLC-MS lipidomics and ERG; involucrin-promoter transgenic rescue of Stgd3 homozygotes with lipid and barrier assays

    PMID:21429867 PMID:22199362

    Open questions at the time
    • Whether VLC-PUFA loss alone is sufficient for photoreceptor degeneration was unclear
    • Brain-specific functions remained unexplored
  8. 2013 High

    Cell-free microsome assays confirmed that truncated ELOVL4 is catalytically dead and dominantly suppresses wild-type enzymatic activity; comparison of conditional KO mice (no degeneration despite VLC-PUFA loss) with STGD3 transgenic mice (degeneration) revealed that mutant protein toxicity, not mere VLC-PUFA deficiency, drives STGD3 retinal dystrophy.

    Evidence Cell-based and microsome condensation assays; rod- and cone-specific conditional KO vs. transgenic STGD3 mice with ERG, GC-MS, and electron microscopy

    PMID:23479632 PMID:23509295

    Open questions at the time
    • The specific toxic mechanism of mislocalized mutant protein in photoreceptors was undefined
    • Whether VLC-PUFA loss contributes to long-term retinal vulnerability remained open
  9. 2014 High

    Active-site mutagenesis established that conserved histidine residues are required for ELOVL4 condensation activity and that ER displacement abolishes enzymatic function, proving the ER microenvironment is essential for catalysis; in Xenopus rods, the truncated mutant mislocalizes to outer segment disks.

    Evidence Overexpression of His-mutant and ER-retention-deficient ELOVL4 with GC-MS elongation assay; transgenic Xenopus photoreceptor imaging

    PMID:24569140 PMID:24833735

    Open questions at the time
    • No crystal structure or detailed catalytic mechanism was available
    • Whether outer-segment disk mislocalization is directly toxic was not shown
  10. 2017 High

    Using skin-rescued Elovl4 mutant mice, ELOVL4-derived VLC-SFAs were shown to regulate synaptic vesicle release kinetics in hippocampal neurons; exogenous VLC-SFA supplementation rescued the defective release rate, establishing a direct role for ELOVL4 lipid products in neurotransmission.

    Evidence Skin-rescued double transgenic mice, hippocampal slice electrophysiology, FM1-43 synaptic vesicle release assay, VLC-SFA rescue experiment

    PMID:29168048

    Open questions at the time
    • The molecular target of VLC-SFA at the synapse (membrane insertion, protein interaction) was unknown
    • Whether VLC-PUFA also contributes to synaptic function was untested
  11. 2018 High

    ELOVL4-derived VLC ceramides were shown to stabilize tight junctions in retinal vascular endothelium, with ELOVL4 overexpression reducing VEGF- and IL-1β-induced permeability and AAV-mediated delivery preventing diabetic retinal vascular leakage in vivo.

    Evidence ELOVL4 overexpression in endothelial cells, permeability assays, EM colocalization with TJ, intravitreal AAV2-hELOVL4 in diabetic mice

    PMID:29362226

    Open questions at the time
    • The precise VLC-ceramide species responsible was not identified
    • Whether this mechanism operates in non-retinal vascular beds was unknown
  12. 2020 High

    The SCA34-causing W246G knock-in rat revealed that ELOVL4 missense mutations selectively impair VLC-SFA synthesis while preserving VLC-PUFA production, dissociating the two product classes and demonstrating that VLC-SFA deficiency alone impairs retinal function without neurodegeneration.

    Evidence W246G knock-in rat with GC/MS lipidomics, ERG, OCT, and histology

    PMID:32780351

    Open questions at the time
    • How a single residue change creates substrate selectivity was structurally unresolved
    • Long-term neurodegeneration over the full lifespan was not fully assessed
  13. 2021 High

    Cerebellar electrophysiology in W246G rats established that SCA34 motor deficits arise from impaired synaptic plasticity—reduced LTP at parallel fiber–Purkinje cell synapses and reduced LTD at climbing fiber–Purkinje cell synapses—rather than from neurodegeneration.

    Evidence Cerebellar slice patch-clamp recordings of LTP and LTD, behavioral motor testing, neuroanatomical analysis in SCA34 knock-in rats

    PMID:34227061

    Open questions at the time
    • Whether VLC-SFA supplementation rescues cerebellar plasticity deficits was not tested
    • The biophysical mechanism by which VLC-SFA modulates plasticity was undefined
  14. 2022 High

    Systematic comparison of SCA34 mutants (L168F, W246G) confirmed that each selectively impairs VLC-SFA biosynthesis while preserving (or even enhancing) VLC-PUFA synthesis, establishing substrate-specific catalytic defects as the molecular basis of SCA34.

    Evidence Cell-based expression of WT, L168F, and W246G ELOVL4 with VLC-FA precursor supplementation and GC-MS quantification

    PMID:36464075

    Open questions at the time
    • No structural explanation for substrate-specific impairment was available
    • Whether VLC-SFA replacement therapy could treat SCA34 was untested
  15. 2023 High

    Multiple SCA34 mutations were mapped to transmembrane helices contacting the ω-end of the substrate acyl-CoA, and all produced incompletely elongated ultra-long-chain PUFA-containing phosphatidylcholines, providing the first structural-mechanistic explanation for SCA34 pathogenesis; detailed electrophysiology further identified pre- and postsynaptic defects including reduced mEPSC frequency, altered paired-pulse ratios, and reduced dendritic spine density in Purkinje cells.

    Evidence Cell-based ULC-PC elongation assay with five SCA34 mutants, structural modeling, knock-in ES cell neuronal differentiation lipidomics; patch-clamp recordings of mEPSC/mIPSC, PPR, and spine morphometry in SCA34-KI rat Purkinje cells

    PMID:36748939 PMID:37491316

    Open questions at the time
    • No experimental 3D structure of ELOVL4 exists
    • Whether incomplete elongation products have toxic gain-of-function effects is unknown
  16. 2023 High

    ELOVL4 was positioned downstream of the NOTCH–RIPK4–IRF6 signaling axis in skin, and conditional Elovl4 deletion alone was sufficient to promote squamous cell carcinoma, revealing a tumor-suppressive function.

    Evidence Autochthonous mouse models with conditional deletion, multiplexed in vivo CRISPR screening, ELOVL4 overexpression rescue in Ripk4-deficient keratinocytes

    PMID:36765696

    Open questions at the time
    • The tumor-suppressive mechanism (lipid product-mediated or cell-autonomous signaling) is uncharacterized
    • Relevance to human SCC is not established
  17. 2025 High

    Testis-specific Elovl4 knockout abolished VLC-PUFA synthesis in testes, causing abnormal spermatogenesis, sperm malformation, decreased motility, and severely reduced male fertility, establishing ELOVL4 as essential for male reproduction.

    Evidence Conditional KO mouse (Elovl4flox/flox; Stra8-Cre) with GC/MS lipid analysis, histology, sperm motility and fertility assays

    PMID:41495266

    Open questions at the time
    • The specific sperm membrane lipid species responsible for motility defects are uncharacterized
    • Whether VLC-PUFA supplementation can rescue fertility is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the three-dimensional structure of ELOVL4 explaining substrate selectivity and SCA34 mutation effects, the molecular mechanism by which VLC-SFAs modulate synaptic vesicle fusion machinery and cerebellar plasticity, and whether lipid replacement therapies can rescue neurological or retinal disease phenotypes.
  • No experimental structure of ELOVL4 or any ELOVL family member exists
  • The biophysical mechanism linking VLC-SFA/PUFA to synaptic vesicle release and plasticity is unknown
  • Therapeutic potential of VLC-FA supplementation or gene therapy for SCA34 and STGD3 is unexplored in clinical settings

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 6 GO:0008289 lipid binding 2
Localization
GO:0005783 endoplasmic reticulum 7
Pathway
R-HSA-1430728 Metabolism 8
Partners
ELOVL1ELOVL2ELOVL5ELOVL6ELOVL7

Evidence

Reading pass · 37 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 very long-chain fatty acid biosynthesis; a 5-bp deletion causing C-terminal truncation segregates with autosomal dominant Stargardt-like macular dystrophy (STGD3) and adMD. Genetic mapping, recombination breakpoint analysis, direct sequencing, bioinformatic homology analysis Nature genetics High 11138005
2004 Wild-type ELOVL4 localizes predominantly to the endoplasmic reticulum (ER) via a C-terminal dilysine (KXKXX) ER-retention/retrieval motif; disease-associated mutations that truncate the C-terminus cause mislocalization to the Golgi in COS-7 and CHO cells, and similarly to the ER in human photoreceptors. Immunofluorescence with organelle markers, immunoelectron microscopy in transfected cells and human photoreceptors Genomics High 15028284
2004 Wild-type ELOVL4 fused to EGFP localizes to the ER; the C-terminally truncated mutant mislocalizes to cytoplasmic aggregates and induces apoptotic cell death in transfected cells. Confocal fluorescence microscopy with ER/mitochondria/peroxisome/Golgi markers, TUNEL staining in NIH 3T3 and HEK293 cells Molecular vision Medium 15073583
2004 A novel Y270X stop mutation in ELOVL4 causes mislocalization of the mutant protein away from the ER in transfected NIH-3T3 and HEK293 cells, consistent with loss of the C-terminal ER-retention signal. EGFP fusion protein transfection, confocal microscopy co-localized with ER marker (pDsRed2-ER) Investigative ophthalmology & visual science Medium 15557430
2005 Disease-associated C-terminal truncation mutants of ELOVL4 accumulate in aggresome-like juxtanuclear inclusions; when co-expressed, mutant ELOVL4 physically interacts with and sequesters wild-type ELOVL4 into these aggresomes, demonstrating a dominant-negative mechanism. Co-immunoprecipitation, immunofluorescence in COS-7 and HEK293T cells The Journal of biological chemistry High 16036915
2005 ELOVL4 mutant protein (5-bp deletion) interacts with wild-type ELOVL4 to form higher molecular mass complexes that accumulate in perinuclear aggresomes, as shown by 2D gel electrophoresis and FRET analysis; mutant protein expression also induces unfolded protein response (BiP and CHOP upregulation). Immunocytochemistry, 2D gel electrophoresis, FRET, western blotting in COS-7 cells Molecular vision High 16163264
2005 ELOVL4 mutants lose ER retention and sequester wild-type ELOVL4 into cytoplasmic aggregates; deletion of the ER retention signal (KAKGD→5A) from wild-type ELOVL4 recapitulates mislocalization; mutant expression induces UPR markers BiP and CHOP. Fluorescence microscopy, co-immunoprecipitation, sucrose gradient fractionation, western blot in HEK293 and COS cells Molecular vision High 16145543
2007 Homozygous loss of ELOVL4 (knock-in 5-bp deletion or full knockout) in mice causes global depletion of very long-chain fatty acids (≥C28) in the epidermis, loss of omega-O-acylceramides, defective lamellar body secretion, disrupted stratum corneum lamellar membranes, and consequent neonatal lethality due to failed epidermal permeability barrier. Knock-in/knockout mouse model, lipid analysis (ceramide/glucosylceramide fractions), electron microscopy of skin ultrastructure, permeability barrier assay Human molecular genetics High 17208947
2007 ELOVL4 knockout (Elovl4-/-) mice lack ceramides with omega-hydroxy very long-chain fatty acids (≥C28), accumulate C26-containing ceramides (implicating C26 as an ELOVL4 substrate), and die postnatally from defective skin water permeability barrier, confirming ELOVL4 is required for C28+ fatty acid synthesis essential for skin barrier. Gene knockout mouse model, lipid analysis, skin histology, electron microscopy, transepidermal water loss measurement International journal of biological sciences High 17311087
2007 Elovl4 Y270X and complete knockout mice die perinatally from dehydration due to defective epidermal permeability barrier; biochemical analysis reveals a significant reduction in free fatty acids longer than C26 in homozygous mutant skin, establishing ELOVL4 as an elongase of C26+ fatty acids. Knock-in/knockout mouse models, fatty acid profiling of skin, transepidermal water loss measurement International journal of biological sciences High 17304340
2007 Stgd3 knock-in mouse retinas show selective deficiency of C32-C36 acyl phosphatidylcholines but no cellular stress response, indicating that lipid product deficiency (rather than ER stress) is the primary pathogenic mechanism in STGD3 retina. Mass spectrometry (lipid profiling) of retina from Stgd3 knock-in mice, ER stress marker analysis FEBS letters Medium 17983602
2008 ELOVL4 is a fatty acid condensing enzyme directly responsible for synthesis of C28-C30 saturated VLC-FA and C28-C38 VLC-PUFA; gain-of-function adenoviral expression of mouse Elovl4 in cardiomyocytes and ARPE-19 cells supplemented with 24:0, 20:5n3, or 22:5n3 produced elongated products up to C30 (saturated) or C38 (PUFA). Gain-of-function adenoviral transduction of Elovl4 in cell lines, fatty acid supplementation, GC-MS lipid analysis Proceedings of the National Academy of Sciences of the United States of America High 18728184
2010 ELOVL4 protein is not involved in DHA (22:6n3) biosynthesis from short-chain precursors (18:3n3 and 22:5n3), as shown by siRNA knockdown in cone photoreceptor-derived 661w cells. siRNA knockdown of ELOVL4 in 661w cells with fatty acid precursor labeling Advances in experimental medicine and biology Medium 20238022
2011 Photoreceptor-specific conditional knockout of Elovl4 in mice causes significant depletion of retinal glycerophospholipids containing VLC-PUFAs (particularly in the sn-1 position of phosphatidylcholine), abnormal lipid droplet and lipofuscin-like granule accumulation, and photoreceptor-specific defects in visual response by ERG. Cre-lox photoreceptor-specific KO mouse, HPLC-MS lipidomics, immunofluorescence, histology, electroretinography The Journal of biological chemistry High 22199362
2011 ELOVL4 preferentially elongates 20:5n3 (EPA) over 20:4n6 or 22:6n3 to produce C28-C38 VLC-PUFA; C34 and C36 VLC-PUFAs are the predominant products; only ELOVL4-expressing cells (not controls) synthesize VLC-PUFA ≥C28 from these precursors. Adenoviral ELOVL4 expression in PC12 cells, fatty acid supplementation, GC-MS lipid analysis Journal of lipid research High 22158834
2011 Epidermal-targeted transgenic expression of wild-type Elovl4 (involucrin promoter) rescues neonatal lethality of homozygous Stgd3 mice, restoring epidermal C28-C36 acylceramides and (O-linoleoyl)-omega-hydroxy C28-C36 fatty acids and skin barrier function, establishing that epidermal ELOVL4-mediated VLC-FA synthesis is essential for survival. Transgenic rescue experiment, lipid analysis, skin barrier function assay Journal of lipid research High 21429867
2013 The STGD3-associated C-terminally truncated ELOVL4 mutant lacks intrinsic condensation (elongase) activity in both cell-based and cell-free microsome assays, and co-expression with wild-type ELOVL4 causes dominant-negative suppression of wild-type ELOVL4 localization and enzymatic activity, reducing VLC-PUFA synthesis. Cell-based and cell-free microsome condensation assays, co-expression experiments, VLC-PUFA quantification by GC-MS Proceedings of the National Academy of Sciences of the United States of America High 23509295
2013 Rod-specific and cone-specific conditional Elovl4 knockout mice show near-total loss of retinal C30-C34 VLC-PUFAs without electrophysiological or behavioral deficits, whereas transgenic mice expressing the human STGD3 mutant ELOVL4 allele develop typical rod-cone dystrophy despite similar VLC-PUFA depletion, suggesting mutant protein toxicity (not VLC-PUFA loss alone) drives the STGD3 phenotype. Conditional KO and transgenic mouse models, GC-MS (VLC-PUFA and A2E measurement), ERG, electron microscopy, optomotor tracking Proceedings of the National Academy of Sciences of the United States of America High 23479632
2014 ELOVL4 elongase activity requires: (1) its localization to the ER microenvironment (displacement from ER abolishes condensation activity); (2) specific active-site histidine residues (His mutants lose elongase activity); N-glycosylation is dispensable for enzyme function. Overexpression of full-length, N-glycosylation-deficient, ER-retention mutant, and active-site histidine mutants of ELOVL4 with VLC-FA elongation assay by GC-MS Journal of lipid research High 24569140
2014 In transgenic Xenopus laevis rod photoreceptors, wild-type ELOVL4 localizes primarily to inner segments; the disease-linked C-terminal truncation mutant (lacking the dilysine ER-retention motif) mislocalizes to post-Golgi compartments and outer segment disks; co-expression of mutant and WT ELOVL4 does not cause mislocalization or aggregation of WT protein in rods in vivo. Transgenic Xenopus laevis rod photoreceptor expression, immunofluorescence and direct fluorescence microscopy Investigative ophthalmology & visual science High 24833735
2014 ELOVL4 is expressed in meibomian gland and sebaceous gland holocrine cells, localizing to structures surrounding lipid deposits; Stgd3 mutant mice show meibomian gland abnormalities including protruding orifices and altered gland anatomy resembling evaporative dry eye, implicating ELOVL4-derived VLC-FAs in meibum composition. Immunohistochemistry in eyelid tissue, histology (H&E), phenotypic assessment in Stgd3 mice Investigative ophthalmology & visual science Medium 24677106
2010 The ELOVL4ΔC (truncation) mutant forms homo-oligomers more strongly than wild-type ELOVL4 and also interacts via hetero-oligomerization with other elongases (ELOVL1-7) and with other VLCFA elongation machinery components, suggesting that ELOVL4ΔC disrupts the entire VLCFA elongation pathway through broad hetero-oligomeric interactions. Co-immunoprecipitation of ELOVL4ΔC with elongases ELOVL1-7 and other elongation complex components in HEK293T cells Molecular vision Medium 21139992
2017 ELOVL4 expression in the brain is restricted primarily to neurons (not astrocytes or radial glia), with expression beginning by embryonic day 18 and persisting in adult cerebral cortex, hippocampus, cerebellum, thalamus, hypothalamus, midbrain, pons, and medulla; some oligodendrocytes in white matter also express ELOVL4; subcellular localization is restricted to cell bodies consistent with ER residence. Immunolabeling with cell-type-specific markers (NeuN, GFAP, Olig2, etc.) in mouse brain sections from E18 to P60 Frontiers in neuroanatomy Medium 28507511
2017 Homozygous expression of the STGD3 Elovl4 mutation (with skin-specific WT rescue) causes seizures by P19 and death by P21 in mice; hippocampal slices show aberrant epileptogenic activity; cultured hippocampal neurons exhibit accelerated synaptic vesicle release kinetics (FM1-43 assay); supplementation with VLC-SFA rescues defective synaptic release to WT rates, establishing that ELOVL4's VLC-SFA products regulate synaptic release kinetics. Double transgenic mouse model with skin rescue, hippocampal slice electrophysiology, FM1-43 dye release assay, VLC-SFA supplementation rescue experiment Molecular neurobiology High 29168048
2018 ELOVL4-derived VLC ceramides (≥C26) stabilize tight junctions in retinal vascular endothelium; ELOVL4 overexpression decreases basal permeability and inhibits VEGF- and IL-1β-induced permeability; ω-linked acyl-VLC ceramides co-localize with tight junction complexes by ultrastructural analysis; intravitreal AAV2-hELOVL4 delivery reduces diabetes-induced retinal vascular permeability. ELOVL4 overexpression in endothelial cells, permeability assays, ultrastructure (EM) and lipidomics, intravitreal AAV delivery in diabetic mice, immunostaining of TJ proteins Diabetes High 29362226
2018 ELOVL4 protein is expressed in spermatocytes during rat spermatogenesis; spermatocytes (with highest ELOVL4 protein levels) are the only testicular cells that produce C26-C32 VLC-PUFAs, directly correlating ELOVL4 enzymatic activity with VLC-PUFA synthesis in germ cells. Western blot, immunohistochemistry, [³H]arachidonate elongation assay in isolated spermatocytes, round spermatids, Sertoli cells; postnatal developmental expression analysis Journal of lipid research Medium 29724783
2020 The SCA34-causing W246G mutant ELOVL4 protein is mislocalized (punctate and aggregated rather than ER-distributed) in patient-derived skin fibroblasts, supporting a dominant-negative effect on protein localization as a pathogenic mechanism. Immunohistochemistry of dermal fibroblasts from patient skin biopsy Neurology. Genetics Medium 32211516
2020 The SCA34-causing W246G ELOVL4 knock-in rat shows selectively impaired VLC-SFA synthesis but preserved VLC-PUFA synthesis in retina and skin; homozygous rats develop reduced ERG a- and b-wave amplitudes without photoreceptor neurodegeneration, revealing a role for VLC-SFA in regulating retinal function independent of neurodegeneration. Knock-in rat model, GC/MS lipid analysis, ERG, OCT, histology, immunolabeling Molecular neurobiology High 32780351
2021 W246G mutant ELOVL4 rats show impaired motor function; cerebellar slice patch-clamp recordings reveal reduced LTP at parallel fiber-Purkinje cell synapses and reduced LTD at climbing fiber-Purkinje cell synapses, with no cerebellar neurodegeneration, establishing that SCA34 motor deficits arise from synaptic plasticity impairment. Knock-in rat model, cerebellar slice electrophysiology (LTP/LTD at PF-PC and CF-PC synapses), behavioral 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), while retaining VLC-PUFA biosynthetic capacity; L168F shows gain-of-function for certain VLC-PUFA species (38:5n3); selective VLC-SFA deficiency may underlie SCA34 and erythrokeratodermia pathology. Cell-based expression of WT, L168F, and W246G ELOVL4 variants with VLC-FA precursor supplementation, GC-MS lipid quantification Journal of lipid research High 36464075
2023 SCA34-causing ELOVL4 mutations (Q180P, T233M, W246G, I171T, L168F) produce shorter ultra-long-chain PUFA-containing phosphatidylcholines (ULC-PCs) than WT, consistent with incomplete elongation; modeled amino acid substitutions are in transmembrane helices that interact with the ω-end of the substrate acyl-CoA; heterozygous Q180P and homozygous W246G knock-in mouse ES cells show reduced neuronal ULC-PC production. Cell-based ULC-PC elongation assay, structural modeling, knock-in mouse ES cell neuronal differentiation, lipidomics Molecular and cellular biology High 36748939
2023 W246G mutant ELOVL4 rat Purkinje cells show reduced mEPSC frequency (presynaptic defect), increased mIPSC frequency and amplitude, reduced paired-pulse ratio at PF-PC but increased at CF-PC synapses, exaggerated persistence of EPSC amplitude (larger readily releasable pool), and reduced dendritic spine density, identifying multiple specific presynaptic and postsynaptic mechanisms of synaptic dysfunction in SCA34. Patch-clamp recordings (mEPSC, mIPSC, PPR, high-frequency stimulation) from cerebellar Purkinje cells of SCA34-KI rats, dendritic spine morphometry The Journal of neuroscience High 37491316
2023 ELOVL4 is a downstream target of the NOTCH-RIPK4-IRF6 signaling axis in skin; loss of Elovl4 alone is sufficient to trigger squamous cell carcinoma (SCC) development in autochthonous mouse models; overexpression of ELOVL4 suppresses tumor growth of Ripk4-deficient keratinocytes. Autochthonous mouse models (Pik3caH1047R oncogene with Ripk4/Irf6/Elovl4 conditional deletion), multiplexed in vivo CRISPR screening, transcriptional profiling, ELOVL4 overexpression rescue in Ripk4-deficient keratinocytes Cancers High 36765696
2021 MYCN transcriptionally represses ELOVL4 in neuroblastoma cells; MYCN binds the ELOVL4 promoter in proximity to HDAC1, HDAC2, and Sp1 (shown by ChIP); ELOVL4 positively regulates neuronal differentiation and lipid droplet accumulation; MYCN silencing increases the ELOVL4 product FA34:6. ChIP (MYCN binding to ELOVL4 promoter), siRNA MYCN knockdown, in vitro differentiation with FA34:6 measurement, reporter assays Oncogene Medium 34333551
2023 Novel ELOVL4 L168S variant causes deficiency in both VLC-SFA and VLC-PUFA biosynthesis (unlike L168F which retains VLC-PUFA synthesis), as demonstrated by cell-based expression with precursor supplementation; associated with early childhood-onset rapidly progressive SCA34 with macular dysfunction. Cell-based expression of L168S ELOVL4 variant with VLC-PUFA and VLC-SFA precursor supplementation, GC-MS lipid quantification Acta neuropathologica communications Medium 37568198
2025 Contact cooling-induced ELOVL4 upregulation in wounded epidermis produces DHA and EPA that dampen TNFα and other pro-inflammatory cytokine expression, accelerating the transition from the inflammatory to the proliferative phase of wound healing; in vivo perturbation of ELOVL4 confirmed its functional requirement. Skin injury and skin organoid models, bulk/scRNA-seq, spatial transcriptomics, in vivo functional perturbation (ELOVL4 KD/OE), cytokine measurement International journal of biological sciences Medium 40083712
2026 Testis-specific knockout of Elovl4 (Stra8-Cre) abolishes VLC-PUFA synthesis (>C26) in testes, causing abnormal spermatogenesis, reduced sperm count, sperm malformation, dramatic changes in Defbs gene family expression, decreased sperm motility, and severely reduced male fertility. Conditional KO mouse (Elovl4flox/flox, Stra8-Cre), GC/MS lipid analysis, spermatogenesis histology, sperm motility assay, fertility testing, RT-PCR and Western blot Scientific reports High 41495266

Source papers

Stage 0 corpus · 97 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 364 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 222 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 134 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 112 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 99 24566826
2019 Novel Cellular Functions of Very Long Chain-Fatty Acids: Insight From ELOVL4 Mutations. Frontiers in cellular neuroscience 87 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 76 22199362
2005 Dominant negative mechanism underlies autosomal dominant Stargardt-like macular dystrophy linked to mutations in ELOVL4. The Journal of biological chemistry 74 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 68 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 60 33556440
2019 Taxonomy and Broad-Spectrum Antifungal Activity of Streptomyces sp. SCA3-4 Isolated From Rhizosphere Soil of Opuntia stricta. Frontiers in microbiology 56 31316480
2007 A Stargardt disease-3 mutation in the mouse Elovl4 gene causes retinal deficiency of C32-C36 acyl phosphatidylcholines. FEBS letters 56 17983602
2005 Loss of ER retention and sequestration of the wild-type ELOVL4 by Stargardt disease dominant negative mutants. Molecular vision 55 16145543
2011 ELOVL4 protein preferentially elongates 20:5n3 to very long chain PUFAs over 20:4n6 and 22:6n3. Journal of lipid research 54 22158834
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 52 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 40 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
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
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 35 29168048
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 32 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
2014 A novel recessive mutation in the gene ELOVL4 causes a neuro-ichthyotic disorder with variable expressivity. BMC medical genetics 30 24571530
2017 Distribution of ELOVL4 in the Developing and Adult Mouse Brain. Frontiers in neuroanatomy 29 28507511
2020 Characterization of the phenotype with cognitive impairment and protein mislocalization in SCA34. Neurology. Genetics 26 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 23 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
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
2022 ELOVL4 Mutations That Cause Spinocerebellar Ataxia-34 Differentially Alter Very Long Chain Fatty Acid Biosynthesis. Journal of lipid research 17 36464075
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
2023 The NOTCH-RIPK4-IRF6-ELOVL4 Axis Suppresses Squamous Cell Carcinoma. Cancers 16 36765696
2021 The expression of ELOVL4, repressed by MYCN, defines neuroblastoma patients with good outcome. Oncogene 16 34333551
2020 The Elovl4 Spinocerebellar Ataxia-34 Mutation 736T>G (p.W246G) Impairs Retinal Function in the Absence of Photoreceptor Degeneration. Molecular neurobiology 16 32780351
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 Elovl4 can effectively elongate C18 polyunsaturated fatty acids in loach Misgurnus anguillicaudatus. Biochemical and biophysical research communications 16 29287723
2021 W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34. Molecular neurobiology 15 34227061
2018 Photoreceptor-induced RPE phagolysosomal maturation defects in Stargardt-like Maculopathy (STGD3). Scientific reports 15 29654292
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 15 29277642
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
2014 Dominant Stargardt Macular Dystrophy (STGD3) and ELOVL4. Advances in experimental medicine and biology 14 24664730
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
2021 Two Italian Patients with ELOVL4-Related Neuro-Ichthyosis:  Expanding the Genotypic and Phenotypic Spectrum and Ultrastructural Characterization. Genes 11 33652762
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 10 37491316
2014 In vivo effect of mutant ELOVL4 on the expression and function of wild-type ELOVL4. Investigative ophthalmology & visual science 10 24644051
2021 Neuropathology of SCA34 showing widespread oligodendroglial pathology with vacuolar white matter degeneration: a case study. Acta neuropathologica communications 9 34689836
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 A novel ELOVL4 variant, L168S, causes early childhood-onset Spinocerebellar ataxia-34 and retinal dysfunction: a case report. Acta neuropathologica communications 7 37568198
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
2018 Elovl4 5-bp deletion does not accelerate cone photoreceptor degeneration in an all-cone mouse. PloS one 6 29293603
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 5 37184663
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
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
2024 The Spinocerebellar Ataxia 34-Causing W246G ELOVL4 Mutation Does Not Alter Cerebellar Neuron Populations in a Rat Model. Cerebellum (London, England) 0 38850484
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