Affinage

ELP1

Elongator complex protein 1 · UniProt O95163

Length
1332 aa
Mass
150.3 kDa
Annotated
2026-04-28
100 papers in source corpus 24 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ELP1 (IKAP) is the largest scaffolding subunit of the Elongator complex, with dual roles in tRNA wobble-uridine modification and transcriptional elongation-coupled histone acetylation, and additional functions in cytoskeletal organization, axonal transport, and neuronal survival. Its C-terminal basic region directly binds tRNA substrates, and phosphorylation of adjacent serine residues by casein kinase I (Hrr25 in yeast) positively regulates Elongator's tRNA modification activity (PMID:24750273, PMID:25569479). In the nervous system, ELP1 loss disrupts microtubule dynamics, target tissue innervation, mitochondrial complex I function, and cilia formation, leading to p53/caspase-3-dependent apoptosis of specific neuronal populations including TrkA+ sensory and sympathetic neurons and retinal ganglion cells (PMID:24173031, PMID:29929962, PMID:28167615, PMID:24917501). A T→C splice-site mutation in IKBKAP intron 20 causes tissue-specific exon 20 skipping—most severe in the nervous system—producing truncated, non-functional protein and causing familial dysautonomia, with exon 20 inclusion governed by opposing activities of SRSF6 (enhanced by CLK-mediated phosphorylation) and inhibitory splicing factors hnRNP A1 and SRSF3 (PMID:11179008, PMID:12577200, PMID:29762696, PMID:34301951).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 High

    Initial identification of IKAP as a putative IκB kinase scaffold raised the question of whether ELP1 functions in NF-κB signaling, but this was definitively refuted when IKAP proved dispensable for IKK activity and NF-κB activation.

    Evidence Biochemical co-purification from IL-1-stimulated cells (1998) followed by quantitative co-IP, antisense knockdown, and in vitro reconstitution showing IKAP is not a stoichiometric IKK component (2000)

    PMID:10893415 PMID:9751059

    Open questions at the time
    • The reason IKAP co-purified with the IKK complex in the original study has not been explained
  2. 2001 High

    Identification of the FD-causing splice-site mutation in IKBKAP intron 20 and the demonstration that tissue-specific exon 20 skipping is most severe in the nervous system established the molecular basis of familial dysautonomia and explained its selective neuronal pathology.

    Evidence Genomic sequencing and RT-PCR in patient lymphoblasts and brain tissues (2001), followed by quantitative tissue-specific splicing ratio analysis across multiple organs (2003)

    PMID:11179008 PMID:11179021 PMID:12577200

    Open questions at the time
    • The trans-acting factors responsible for tissue-specific splicing efficiency were not yet identified
    • Why the nervous system has the lowest WT:mutant transcript ratio was not mechanistically explained
  3. 2003 High

    Characterization of the weak intrinsic splicing signals flanking exon 20 explained why the position-6 splice-site mutation causes exon skipping specifically in this context, establishing a cis-regulatory framework for the FD splicing defect.

    Evidence Computational splice-site analysis combined with in vitro RNAPII-coupled transcription/splicing assay and minigene transfection

    PMID:16964593

    Open questions at the time
    • Identity of tissue-specific trans-acting splicing regulators was still unknown
  4. 2008 High

    Discovery that ELP1 localizes to membrane ruffles with filamin A and that its loss disrupts cell adhesion, migration, and actin organization established a direct cytoskeletal role beyond transcriptional functions.

    Evidence RNAi knockdown with rescue by wild-type but not FD-truncated IKAP in multiple cell types including primary neurons; co-purification with filamin A

    PMID:18303054

    Open questions at the time
    • Whether cytoskeletal defects are direct or secondary to tRNA modification/translational defects was not resolved
  5. 2008 High

    Knockout studies in mice proved ELP1 is essential for embryonic viability and linked its loss to defective transcriptional elongation-coupled histone acetylation, establishing the Elongator complex function as physiologically critical in mammals.

    Evidence Ikbkap-null and exon-20-deletion mice showing embryonic lethality with vascular/neural defects; histone acetylation assay and transgenic rescue

    PMID:19015235 PMID:22046433

    Open questions at the time
    • Relative contributions of histone acetylation versus tRNA modification to the embryonic phenotype were not disentangled
  6. 2013 High

    Cell-type-specific conditional knockouts revealed that ELP1 is essential for TrkA+ nociceptor neurogenesis and survival via suppression of p53-mediated premature differentiation and caspase-3-dependent apoptosis, explaining the selective sensory neuron loss in FD.

    Evidence PNS-specific Ikbkap conditional KO with caspase-3 immunostaining, neuronal subtype counting, and genetic epistasis

    PMID:24173031

    Open questions at the time
    • How ELP1 loss activates p53 was not determined
    • Whether the apoptosis mechanism differs between sensory and sympathetic neurons was not resolved
  7. 2013 High

    A conserved tRNA wobble-uridine modification function was confirmed in mammals when Ikbkap-mutant testes showed tRNA modification defects alongside meiotic failure, and yeast studies mapped this activity to direct tRNA binding by the Elp1 C-terminal basic region.

    Evidence Spermatocyte-specific conditional KO with tRNA modification analysis (2013); alanine mutagenesis of Elp1 C-terminal domain with direct tRNA binding assay in yeast (2014)

    PMID:23717213 PMID:24750273

    Open questions at the time
    • Whether tRNA modification defects directly cause the meiotic phenotype or act through downstream translational effects was not tested
  8. 2014 High

    ELP1 was shown to regulate microtubule dynamics and axonal transport in neurons: its loss disrupts tyrosinated α-tubulin distribution and target innervation in sympathetic neurons, and it colocalizes with dynein and pJNK at axon terminals to facilitate retrograde signaling.

    Evidence Conditional KO of Elp1 in post-migratory sympathetic neurons with tubulin immunostaining; shRNA knockdown in chick DRG neurons with JNK signaling analysis

    PMID:24917501 PMID:25409162

    Open questions at the time
    • Direct reconstitution of an ELP1-dynein transport complex has not been achieved
    • Whether cytoskeletal defects reflect tRNA-modification-dependent translational effects on tubulin-modifying enzymes is unresolved
  9. 2015 High

    Phosphorylation of Elp1 by casein kinase I Hrr25 at C-terminal serines adjacent to the tRNA-binding region was shown to positively regulate Elongator tRNA modification activity, establishing a regulatory switch controlling Elongator function.

    Evidence In vitro kinase assay with Hrr25, mass-spectrometry-based phosphosite mapping, phosphomimetic/alanine substitutions with tRNA modification functional readout in yeast

    PMID:25569479

    Open questions at the time
    • Whether the mammalian orthologous kinase CK1 performs the equivalent regulation has not been tested
    • How phosphorylation mechanistically alters tRNA binding or catalysis is unknown
  10. 2017 High

    CNS-specific ELP1 functions were uncovered: conditional deletion disrupts cortical neuron development, primary and motile cilia formation, and causes progressive motor and cortical neurodegeneration, broadening FD pathology beyond the PNS.

    Evidence Nervous-system-specific conditional KO mouse with cilia morphology analysis, neuron counting, and behavioral assays

    PMID:28167615

    Open questions at the time
    • Mechanism linking ELP1 to ciliogenesis is unknown
    • Whether cilia defects contribute to neurodegeneration or are parallel consequences is unclear
  11. 2018 High

    ELP1 loss was linked to selective mitochondrial dysfunction: retinal ganglion cells lacking IKAP show mitochondrial membrane depolarization and impaired complex I activity, revealing a mitochondrial vulnerability mechanism for neurodegeneration.

    Evidence Retina-specific conditional KO with mitochondrial membrane potential, complex I activity, and ATP measurements

    PMID:29929962

    Open questions at the time
    • Whether mitochondrial dysfunction is a direct consequence of tRNA hypomodification or an indirect effect is not established
    • Generalizability of the mitochondrial mechanism to other neuron types in FD is untested
  12. 2018 High

    The trans-acting splicing regulatory landscape of IKBKAP exon 20 was defined: hnRNP A1 was identified as a negative regulator binding intronic silencer elements, and antisense oligonucleotides targeting these regulatory regions fully restored exon 20 splicing in patient cells and FD mouse CNS.

    Evidence RNA binding assays, site-directed mutagenesis, hnRNP A1 knockdown in FD fibroblasts; two-step ASO screen with in vivo administration in FD transgenic mice

    PMID:29672717 PMID:29762696

    Open questions at the time
    • Long-term therapeutic efficacy and safety of ASOs in FD patients was not assessed
    • Whether hnRNP A1 contributes to tissue-specific splicing variation was not determined
  13. 2021 High

    The positive splicing regulator SRSF6 and its upstream CLK kinases were identified as the mechanistic targets through which exon 20 inclusion can be pharmacologically enhanced, completing a bidirectional model of exon 20 splicing regulation.

    Evidence SRSF6 knockdown, direct RECTAS-CLK binding assay, SRSF6 phosphorylation assay, minigene and patient-derived cell line validation

    PMID:34301951

    Open questions at the time
    • Whether CLK-SRSF6 activity differs across tissues and explains tissue-specific splicing ratios is not known
    • Therapeutic window for CLK modulation in patients is undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how ELP1 loss mechanistically activates p53 in neuronal progenitors, whether the cytoskeletal and mitochondrial defects are primary consequences of tRNA hypomodification or represent independent functions, and what determines the cell-type-selective vulnerability to ELP1 deficiency across different neuronal populations.
  • No structural model of the full mammalian Elongator complex with tRNA substrate
  • Causal hierarchy among tRNA modification, translational fidelity, cytoskeletal, and mitochondrial phenotypes is unresolved
  • Molecular basis of cell-type-specific vulnerability (e.g., TrkA+ vs TrkC+ neurons) is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2 GO:0003723 RNA binding 1
Localization
GO:0005856 cytoskeleton 4 GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-1643685 Disease 6 R-HSA-1266738 Developmental Biology 5 R-HSA-8953854 Metabolism of RNA 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
ELP3FLNAHNRNPA1HRR25KTI12SRSF3SRSF6
Complex memberships
Elongator complex

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 IKAP (ELP1) was identified as a scaffold protein of the IκB kinase complex, capable of binding NIK, IKK-α, and IKK-β and assembling them into an active kinase complex, as demonstrated by isolation of large IL-1-inducible IKK complexes containing NIK, IKK-α, IKK-β, IκB-α, NF-κB/RelA, and IKAP. Biochemical co-purification and complex isolation from IL-1-stimulated cells; protein identification by mass spectrometry Nature Medium 9751059
2000 IKAP is not a stoichiometric component of the IKK complex and plays no specific role in cytokine-induced NF-κB activation; IKKγ/NEMO was identified as the obligatory scaffold subunit. Antisense-mediated reduction of IKAP had no effect on IKK activity or NF-κB signaling, whereas IKKγ reduction did. Quantitative co-immunoprecipitation, antisense oligonucleotide knockdown, NF-κB reporter assay, in vitro reconstitution of IKK complex with IKKα/β/γ only The Journal of biological chemistry High 10893415
2001 The major FD-causing mutation is a T→C transition at the donor splice site of intron 20 of IKBKAP, resulting in tissue-specific skipping of exon 20 and production of a truncated, non-functional IKAP protein; a minor missense mutation R696P in exon 19 disrupts a consensus serine/threonine kinase phosphorylation site and causes defective phosphorylation of IKAP. Genomic sequencing, RT-PCR, tissue-specific RNA analysis from lymphoblasts and brain, protein analysis American journal of human genetics High 11179008 11179021
2003 Tissue-specific reduction in wild-type IKBKAP splicing efficiency underlies the selective neuronal degeneration in FD; WT:mutant IKBKAP transcript ratios are highest in lymphoblasts and lowest in postmortem central and peripheral nervous tissues, with corresponding reduction in WT IKAP protein. Densitometry and real-time quantitative PCR on RNA from lymphoblasts, fibroblasts, blood, and postmortem tissues; immunoblotting for protein American journal of human genetics High 12577200
2003 Weak intrinsic splicing signals flanking IKBKAP exon 20 (weak 3' splice site and weak exonic sequences) underlie the FD splicing defect; the position-6 mutation in the 5' splice site causes exon skipping only in the context of these pre-existing weak signals, as validated by in vitro coupled RNAPII transcription/splicing assay and minigene transfection. Computational splice-site analysis, in vitro RNAPII-coupled transcription/splicing assay, minigene transfection assays Human mutation High 16964593
2008 IKAP (ELP1) localizes to membrane ruffles where it co-localizes with filamin A; RNAi-mediated depletion of IKAP causes defective cell adhesion, migration, and actin cytoskeleton organization in multiple cell types including primary neurons, effects rescued by wild-type IKAP but not by the FD-truncated form. RNAi knockdown, immunostaining, co-purification with filamin A, rescue experiments with wild-type vs. FD-IKAP, migration assays Journal of cell science High 18303054
2008 Loss of Ikbkap in mouse embryos causes embryonic lethality by E12.5 with defects in vascular and neural development; Ikbkap-null embryos show downregulation of genes important for neurulation and vascular development correlated with a defect in transcriptional elongation-coupled histone acetylation. Conditional knockout mouse, morphological analysis, microarray/gene expression analysis, histone acetylation assay, rescue with human IKBKAP transgene Molecular and cellular biology High 19015235
2011 IKAP/Elp1 deficiency causes disorganization of microtubules and aberrant cell shape; SCG10 (STMN2), a microtubule-destabilizing protein, is upregulated in IKAP-deficient cells, and REST (a repressor of SCG10) is downregulated in IKAP-deficient neuroblastoma cells and FD cerebrum, providing a mechanistic link between IKAP deficiency and cytoskeletal destabilization. Immunostaining of α-tubulin in IKAP knockdown cell lines and FD tissues, western blot and RT-PCR for SCG10 and REST in FD cerebrum and fibroblasts Human molecular genetics Medium 21273291
2011 Deletion of exon 20 of Ikbkap abolishes gene function, causing developmental delay, cardiovascular defects, and early embryonic lethality; IKAP is essential for expression of specific genes involved in cardiac morphogenesis, and the FD-truncated protein lacks significant biological function. Homologous recombination to generate exon-20 deletion allele in mice, embryological analysis, gene expression profiling PloS one High 22046433
2012 IKAP/Elp1 is not required for neural crest cell migration but is essential for post-migratory neuronal differentiation and survival; gain- and loss-of-function studies in chick embryos show IKAP is expressed as neurons differentiate and that altered IKAP levels perturb neuronal polarity, differentiation, and survival. RNAi knockdown in neural crest lineage in ovo, gain-of-function overexpression, reporter gene analysis, immunostaining for IKAP expression pattern PloS one High 22384137
2013 Ikbkap is essential for the second wave of neurogenesis producing TrkA+ nociceptors and thermoreceptors; in its absence, Pax3+ progenitors undergo p53-mediated premature differentiation and death, and TrkA+ (but not TrkC+) sensory and sympathetic neurons undergo exacerbated caspase-3-mediated apoptosis independent of NGF levels. Conditional knockout (PNS-specific Ikbkap deletion), immunostaining, apoptosis assays (caspase-3), neuronal counting, genetic epistasis Proceedings of the National Academy of Sciences of the United States of America High 24173031
2013 Ikbkap/Elp1 is essential for meiosis during spermatogenesis; absence causes defects in synapsis and meiotic recombination leading to apoptosis and complete gametogenesis arrest. Additionally, Ikbkap-mutant testes show defects in wobble uridine tRNA modification, confirming a conserved tRNA modification function from yeast to mammals. Conditional knockout mouse (spermatocyte-specific), cytological analysis of meiotic spread chromosomes, tRNA modification analysis, gene expression profiling PLoS genetics High 23717213
2014 Elp1 (ELP1) loss in post-migratory sympathetic neurons causes failed target tissue innervation correlated with abnormal neurite outgrowth/branching and abnormal cellular distribution of soluble tyrosinated α-tubulin, indicating a role for Elp1 in cytoskeletal regulation required for innervation. Conditional knockout of Elp1 in neural crest progenitors and post-migratory sympathetic neurons, immunostaining for tyrosinated α-tubulin, neurite morphology analysis Development (Cambridge, England) High 24917501
2014 IKAP colocalizes with activated JNK (pJNK), dynein, and β-tubulin at axon terminals of DRG neurons, and is required for transport of specific target-derived signals for JNK and NGF responsive gene transcription in the nucleus. Immunostaining and colocalization analysis in chick DRG neurons; shRNA knockdown of IKAP followed by JNK signaling and gene expression analysis PloS one Medium 25409162
2014 The C-terminal basic (arginine/lysine-rich) region of yeast Elp1 is essential for Elongator tRNA wobble uridine modification function by mediating a direct interaction between tRNA and the Elp1 C-terminal domain, rather than controlling nucleo-cytoplasmic distribution. Alanine substitution mutagenesis, tRNA modification assays, tRNA-binding assays with Elp1 C-terminal domain, subcellular fractionation Molecular microbiology High 24750273
2015 The yeast casein kinase I Hrr25 directly phosphorylates Elp1 on Ser-1198 and Ser-1202 at its C-terminus adjacent to the tRNA-binding region; phosphorylation at these sites positively regulates Elongator's tRNA modification function and modulates interactions with accessory protein Kti12 and Hrr25 itself. In vivo phosphorylation site mapping (mass spectrometry), in vitro kinase assay with Hrr25, alanine and phosphomimetic substitutions at identified sites, tRNA modification functional assays PLoS genetics High 25569479
2017 Ikbkap is required not only in the PNS but also in the CNS; conditional deletion in the nervous system disrupts cortical neuron development and survival, reduces primary cilia in embryonic cortical apical progenitors and motile cilia in adult ependymal cells, and causes progressive loss of spinal motor and cortical neurons. Nervous-system-specific conditional knockout mouse, immunostaining, neuron counting, cilia morphology analysis, behavioral assays Disease models & mechanisms High 28167615
2018 Loss of IKAP in retinal ganglion cells causes mitochondrial membrane depolarization, impaired complex I function, and reduced ATP, leading to selective RGC degeneration; other retinal neurons show mitochondrial impairment but do not degenerate, implicating RGC-specific mitochondrial vulnerability. Retina-specific conditional knockout (Pax6-Cre), mitochondrial membrane potential assay, complex I activity assay, ATP measurement, immunostaining, cell counting Disease models & mechanisms High 29929962
2018 hnRNP A1 binds to an intronic splicing silencer downstream of the IKBKAP exon 20 5' splice site and to two inhibitory intronic splicing elements inside exon 20, acting as a negative regulator of exon 20 inclusion; knockdown of hnRNP A1 increases exon 20 inclusion in FD patient cells. RNA binding assays, site-directed mutagenesis of SREs in minigene, hnRNP A1 knockdown in FD patient fibroblasts, splice-switching oligonucleotides blocking hnRNP A1 binding site Nucleic acids research High 29762696
2018 Antisense oligonucleotides targeting intronic regions adjacent to IKBKAP exon 20 can fully restore exon 20 splicing in FD patient fibroblasts and increase full-length IKAP protein in multiple tissues including CNS of FD transgenic mice; cis-acting regulatory sequences controlling exon 20 recognition were characterized. Two-step ASO screen, minigene splicing assays, ASO administration in FD transgenic mice, RT-PCR and western blot for IKBKAP mRNA and IKAP protein in multiple tissues Nucleic acids research High 29672717
2021 Exon 20 inclusion in IKBKAP is promoted by SRSF6 binding to an intronic splicing enhancer in intron 20; the small molecule RECTAS directly interacts with CDC-like kinases (CLKs) and enhances SRSF6 phosphorylation, thereby promoting exon 20 inclusion. Conversely, CLK inhibition reduces exon 20 splicing, and exon 20 splicing can be bidirectionally manipulated by targeting CLK activity. Knockdown of SRSF6 and other SR proteins, direct binding assay of RECTAS to CLKs, phosphorylation assays for SRSF6, minigene splicing assays, patient-derived cell lines and FD disease models Nature communications High 34301951
2012 SKF-86466 (an alpha-2 adrenergic receptor antagonist) rescues IKBKAP expression in FD iPSC-derived neural crest precursors by inducing IKBKAP transcription through modulation of intracellular cAMP levels and PKA-dependent CREB phosphorylation, implicating the alpha-2 adrenergic receptor/cAMP/PKA/CREB pathway in regulating IKBKAP expression. iPSC-derived neural crest precursor screen of 6,912 compounds, cAMP measurement, PKA inhibitor experiments, CREB phosphorylation assay, IKAP protein rescue assay Nature biotechnology High 23159879
2013 Cardiac glycoside digoxin corrects FD-associated aberrant IKBKAP splicing by suppressing SRSF3 protein levels; SRSF3 binding site(s) in the intron 5' of exon 20 are required for this effect, identifying SRSF3 as a negative regulator of exon 20 inclusion. RT-PCR splicing assay, SRSF3 knockdown, cis-element mutagenesis, digoxin treatment in FD patient cells and neuronal cells The FEBS journal Medium 23711097

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. American journal of human genetics 467 11179008
2001 Familial dysautonomia is caused by mutations of the IKAP gene. American journal of human genetics 344 11179021
2019 Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet. Frontiers in physiology 253 31130874
1998 IKAP is a scaffold protein of the IkappaB kinase complex. Nature 243 9751059
2009 Mitochondrial (dys)function in adipocyte (de)differentiation and systemic metabolic alterations. The American journal of pathology 205 19700756
2012 Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression. Nature biotechnology 177 23159879
2005 Auditory neuropathy/dys-synchrony and its perceptual consequences. Trends in amplification 164 15920648
2014 Sex differences in mitochondrial (dys)function: Implications for neuroprotection. Journal of bioenergetics and biomembranes 159 25293493
1992 A brefeldin A-like phenotype is induced by the overexpression of a human ERD-2-like protein, ELP-1. Cell 144 1316805
2013 Rho-kinase: regulation, (dys)function, and inhibition. Biological chemistry 143 23950574
2003 Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia. American journal of human genetics 117 12577200
2010 Sodium channel (dys)function and cardiac arrhythmias. Cardiovascular therapeutics 112 20645984
2008 Loss of mouse Ikbkap, a subunit of elongator, leads to transcriptional deficits and embryonic lethality that can be rescued by human IKBKAP. Molecular and cellular biology 105 19015235
2015 MicroRNAs and Endothelial (Dys) Function. Journal of cellular physiology 104 26627535
2012 Crosstalk between mitochondrial (dys)function and mitochondrial abundance. Journal of cellular physiology 104 21928343
2015 The facts about sexual (Dys)function in schizophrenia: an overview of clinically relevant findings. Schizophrenia bulletin 101 25721311
2015 Cholestatic liver (dys)function during sepsis and other critical illnesses. Intensive care medicine 99 26392257
1998 Mutations in the Caenorhabditis elegans dystrophin-like gene dys-1 lead to hyperactivity and suggest a link with cholinergic transmission. Neurogenetics 99 9933302
2000 The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component. The Journal of biological chemistry 98 10893415
2008 IKAP localizes to membrane ruffles with filamin A and regulates actin cytoskeleton organization and cell migration. Journal of cell science 91 18303054
2003 Auditory neuropathy/dys-synchrony: diagnosis and management. Mental retardation and developmental disabilities research reviews 84 14648814
2011 Kinetin improves IKBKAP mRNA splicing in patients with familial dysautonomia. Pediatric research 81 21775922
2019 Human sperm ion channel (dys)function: implications for fertilization. Human reproduction update 79 31665287
2008 Emotion (Dys)regulation and Links to Depressive Disorders. Child development perspectives 78 20721304
2015 The (dys)functional extracellular matrix. Biochimica et biophysica acta 75 25930943
2004 HERG channel (dys)function revealed by dynamic action potential clamp technique. Biophysical journal 72 15475579
2003 EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with familial dysautonomia. Biochemical and biophysical research communications 70 14521957
2009 The ubiquitin-proteasome pathway and endothelial (dys)function. Cardiovascular research 68 19767293
2014 A neuron autonomous role for the familial dysautonomia gene ELP1 in sympathetic and sensory target tissue innervation. Development (Cambridge, England) 66 24917501
2013 Using neurolipidomics to identify phospholipid mediators of synaptic (dys)function in Alzheimer's Disease. Frontiers in physiology 66 23882219
2008 The Krüppel-like factor 9 (KLF9) network in HEC-1-A endometrial carcinoma cells suggests the carcinogenic potential of dys-regulated KLF9 expression. Reproductive biology and endocrinology : RB&E 64 18783612
2013 Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3+ progenitors and peripheral neurons. Proceedings of the National Academy of Sciences of the United States of America 61 24173031
2003 Tocotrienols induce IKBKAP expression: a possible therapy for familial dysautonomia. Biochemical and biophysical research communications 59 12788105
2017 Genomics of Islet (Dys)function and Type 2 Diabetes. Trends in genetics : TIG 58 28245910
2015 IKAP: A heuristic framework for inference of kinase activities from Phosphoproteomics data. Bioinformatics (Oxford, England) 58 26628587
2009 Beta cell (dys)function in non-diabetic offspring of diabetic patients. Diabetologia 58 19756484
2023 Neutrophil (dys)function due to altered immuno-metabolic axis in type 2 diabetes: implications in combating infections. Human cell 55 37115481
2017 Mitochondrial (Dys) Function in Inflammaging: Do MitomiRs Influence the Energetic, Oxidative, and Inflammatory Status of Senescent Cells? Mediators of inflammation 55 29445253
2002 Superantigen-like gene(s) in human pathogenic Streptococcus dysgalactiae, subsp equisimilis: genomic localisation of the gene encoding streptococcal pyrogenic exotoxin G (speG(dys)). FEMS immunology and medical microbiology 54 12381468
2011 IKAP/Elp1 involvement in cytoskeleton regulation and implication for familial dysautonomia. Human molecular genetics 52 21273291
2018 Antisense oligonucleotides correct the familial dysautonomia splicing defect in IKBKAP transgenic mice. Nucleic acids research 51 29672717
2007 A humanized IKBKAP transgenic mouse models a tissue-specific human splicing defect. Genomics 51 17644305
2005 Quantitative proton MRS of Pelizaeus-Merzbacher disease: evidence of dys- and hypomyelination. Neurology 51 16157902
2011 MicroRNAs and vascular (dys)function. Vascular pharmacology 50 21802526
2008 Uncovering genes for cognitive (dys)function and predisposition for alcoholism spectrum disorders: a review of human brain oscillations as effective endophenotypes. Brain research 50 18634760
2013 Differential recruitment of coregulators to the RORA promoter adds another layer of complexity to gene (dys) regulation by sex hormones in autism. Molecular autism 49 24119295
2010 OPA1 (dys)functions. Seminars in cell & developmental biology 49 20045077
2002 Familial dysautonomia: detection of the IKBKAP IVS20(+6T --> C) and R696P mutations and frequencies among Ashkenazi Jews. American journal of medical genetics 49 12116234
2013 Ikbkap/Elp1 deficiency causes male infertility by disrupting meiotic progression. PLoS genetics 47 23717213
2007 IKAP/hELP1 deficiency in the cerebrum of familial dysautonomia patients results in down regulation of genes involved in oligodendrocyte differentiation and in myelination. Human molecular genetics 44 17591626
2016 Histone acetylation in neuronal (dys)function. Biomolecular concepts 43 27101554
2005 Connexin 26 variants and auditory neuropathy/dys-synchrony among children in schools for the deaf. American journal of medical genetics. Part A 42 16222667
2003 Patients with auditory neuropathy/dys-synchrony lack efferent suppression of transient evoked otoacoustic emissions. Journal of the American Academy of Audiology 42 14552424
2015 Phosphorylation of Elp1 by Hrr25 is required for elongator-dependent tRNA modification in yeast. PLoS genetics 41 25569479
2007 Weak definition of IKBKAP exon 20 leads to aberrant splicing in familial dysautonomia. Human mutation 41 16964593
2019 ELP1 Splicing Correction Reverses Proprioceptive Sensory Loss in Familial Dysautonomia. American journal of human genetics 39 30905397
2010 Phosphatidylserine increases IKBKAP levels in familial dysautonomia cells. PloS one 39 21209961
2015 Liver Disease and Hemostatic (Dys)function. Seminars in thrombosis and hemostasis 38 26080306
2012 The CXCR3(+)CD56Bright phenotype characterizes a distinct NK cell subset with anti-fibrotic potential that shows dys-regulated activity in hepatitis C. PloS one 38 22792160
2012 IKAP/Elp1 is required in vivo for neurogenesis and neuronal survival, but not for neural crest migration. PloS one 37 22384137
2021 Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia. Nature communications 36 34301951
2014 Transcriptional dys-regulation in anxiety and major depression: 5-HT1A gene promoter architecture as a therapeutic opportunity. Current pharmaceutical design 36 24180393
2014 Involvement of IKAP in peripheral target innervation and in specific JNK and NGF signaling in developing PNS neurons. PloS one 36 25409162
2012 Exon 45 skipping through U1-snRNA antisense molecules recovers the Dys-nNOS pathway and muscle differentiation in human DMD myoblasts. Molecular therapy : the journal of the American Society of Gene Therapy 36 22968481
2011 Deletion of exon 20 of the Familial Dysautonomia gene Ikbkap in mice causes developmental delay, cardiovascular defects, and early embryonic lethality. PloS one 36 22046433
2006 Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination. Neurogenetics 36 16969684
2013 Late sodium current inhibition in acquired and inherited ventricular (dys)function and arrhythmias. Cardiovascular drugs and therapy 35 23292167
2014 Mitochondria: mitochondrial OXPHOS (dys) function ex vivo--the use of primary fibroblasts. The international journal of biochemistry & cell biology 34 24412346
2014 Genetic dys-regulation of astrocytic glutamate transporter EAAT2 and its implications in neurological disorders and manganese toxicity. Neurochemical research 34 25064045
2017 The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system. Disease models & mechanisms 33 28167615
2017 ASK1 (MAP3K5) is transcriptionally upregulated by E2F1 in adipose tissue in obesity, molecularly defining a human dys-metabolic obese phenotype. Molecular metabolism 31 28702328
2013 Phosphatidylserine increases IKBKAP levels in a humanized knock-in IKBKAP mouse model. Human molecular genetics 31 23515154
2012 Recent developments in the regulation of monoamine oxidase form and function: is the current model restricting our understanding of the breadth of contribution of monoamine oxidase to brain [dys]function? Current topics in medicinal chemistry 31 23231394
2022 Structural (dys)connectivity associates with cholinergic cell density in Alzheimer's disease. Brain : a journal of neurology 28 35259207
2016 Loss of Ikbkap Causes Slow, Progressive Retinal Degeneration in a Mouse Model of Familial Dysautonomia. eNeuro 28 27699209
2013 Mitochondrial (dys)function and regulation of macrophage cholesterol efflux. Clinical science (London, England : 1979) 27 23298226
2006 Pacing-induced dys-synchrony preconditions rabbit myocardium against ischemia/reperfusion injury. Circulation 26 16820583
2013 S-glutathionylation in monocyte and macrophage (dys)function. International journal of molecular sciences 25 23887649
2005 Tocotrienols reverse IKAP and monoamine oxidase deficiencies in familial dysautonomia. Biochemical and biophysical research communications 25 16125677
1999 Mutations in the dystrophin-like dys-1 gene of Caenorhabditis elegans result in reduced acetylcholinesterase activity. FEBS letters 25 10606735
2008 The C. elegans EMAP-like protein, ELP-1 is required for touch sensation and associates with microtubules and adhesion complexes. BMC developmental biology 24 19014691
2001 Cloning, characterization, and genomic structure of the mouse Ikbkap gene. DNA and cell biology 24 11747609
2018 Early Retinal Defects in Fmr1-/y Mice: Toward a Critical Role of Visual Dys-Sensitivity in the Fragile X Syndrome Phenotype? Frontiers in cellular neuroscience 22 29681800
2018 Retina-specific loss of Ikbkap/Elp1 causes mitochondrial dysfunction that leads to selective retinal ganglion cell degeneration in a mouse model of familial dysautonomia. Disease models & mechanisms 22 29929962
2015 Familial Dysautonomia (FD) Human Embryonic Stem Cell Derived PNS Neurons Reveal that Synaptic Vesicular and Neuronal Transport Genes Are Directly or Indirectly Affected by IKBKAP Downregulation. PloS one 22 26437462
2005 Lack of mitogenic activity of speG- and speG(dys)-positive Streptococcus dysgalactiae subspecies equisimilis isolates from patients with invasive infections. International journal of medical microbiology : IJMM 22 16325550
2003 Of splice and men: what does the distribution of IKAP mRNA in the rat tell us about the pathogenesis of familial dysautonomia? Brain research 22 12914982
2022 From the Structural and (Dys)Function of ATP Synthase to Deficiency in Age-Related Diseases. Life (Basel, Switzerland) 21 35330152
2018 Development of a Screening Platform to Identify Small Molecules That Modify ELP1 Pre-mRNA Splicing in Familial Dysautonomia. SLAS discovery : advancing life sciences R & D 21 30085848
1997 Characterization of IKI1 and IKI3 genes conferring pGKL killer sensitivity on Saccharomyces cerevisiae. Bioscience, biotechnology, and biochemistry 21 9145530
2014 A conserved and essential basic region mediates tRNA binding to the Elp1 subunit of the Saccharomyces cerevisiae Elongator complex. Molecular microbiology 20 24750273
2013 Cardiac glycosides correct aberrant splicing of IKBKAP-encoded mRNA in familial dysautonomia derived cells by suppressing expression of SRSF3. The FEBS journal 20 23711097
2015 Molecular characterization of 7 patients affected by dys- or hypo-dysfibrinogenemia: Identification of a novel mutation in the fibrinogen Bbeta chain causing a gain of glycosylation. Thrombosis research 19 26006300
2011 Sickle cell, habitual dys-positions and fragile dispositions: young people with sickle cell at school. Sociology of health & illness 19 21375541
2009 Dys-regulated activation of a Src tyroine kinase Hck at the Golgi disturbs N-glycosylation of a cytokine receptor Fms. Journal of cellular physiology 19 19585521
2014 Astragalus membranaceus up-regulate Cosmc expression and reverse IgA dys-glycosylation in IgA nephropathy. BMC complementary and alternative medicine 18 24942185
2008 Loss-of-function of IKAP/ELP1: could neuronal migration defect underlie familial dysautonomia? Cell adhesion & migration 18 19262150
2022 Redox stress and metal dys-homeostasis appear as hallmarks of early prion disease pathogenesis in mice. Free radical biology & medicine 17 36170956
2018 Blocking of an intronic splicing silencer completely rescues IKBKAP exon 20 splicing in familial dysautonomia patient cells. Nucleic acids research 17 29762696
2016 MicroRNA screening identifies a link between NOVA1 expression and a low level of IKAP in familial dysautonomia. Disease models & mechanisms 17 27483351