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Gene Review

IKBKAP  -  inhibitor of kappa light polypeptide gene...

Homo sapiens

Synonyms: DYS, ELP1, Elongator complex protein 1, FD, IKAP, ...
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Disease relevance of IKBKAP


Psychiatry related information on IKBKAP

  • Axis I diagnoses were present in 74.8% of the participants overall with the DYS subgroup mainly reporting anxiety and the ID group mood disorders [6].

High impact information on IKBKAP

  • This latter component is a new protein, termed IKK-complex-associated protein (IKAP), which can bind NIK and IKKs and assemble them into an active kinase complex [7].
  • Mutations in IKBKAP, encoding a subunit of Elongator, cause familial dysautonomia (FD), a severe neurodevelopmental disease with complex clinical characteristics [8].
  • Indeed, characterization of IKAP/hELP1 RNAi cells, FD fibroblasts, and neuronal cell-derived cells uncovered defects in this cellular function upon Elongator depletion [8].
  • In vitro, the head domains of CLIP-170 and of p150 Glued bind more efficiently to tyrosinated microtubules than to detyrosinated polymers [9].
  • Here, we show that fasciata1-4 (fas1-4), a new allele of the Arabidopsis fas1 mutant defective in the p150 subunit of CAF-1, has a severe developmental phenotype, reduced heterochromatin content, and a more open conformation of euchromatin [10].

Biological context of IKBKAP


Anatomical context of IKBKAP

  • We consistently found that WT IKBKAP transcripts were present, albeit to varying extents, in all cell lines, blood, and postmortem FD tissues [14].
  • Here, we have further characterized the consequences of the major mutation by examining the ratio of wild-type to mutant (WT:MU) IKBKAP transcript in EBV-transformed lymphoblast lines, primary fibroblasts, freshly collected blood samples, and postmortem tissues from patients with FD [14].
  • The hVPS34/p150 complex colocalized with rab7 on late endosomes and hVPS34 activity was dependent on nucleotide cycling of rab7 [15].
  • Cleavage of MP1 and release of a 150-kDa intermediate, p150, are likely to be important for embedding the replicase complex in cellular membranes [16].
  • We examined 201 regions from 47 patients that represented different stages of esophageal neoplasia, comprising 34 areas of normal mucosa, 18 of dysplasia in squamous epithelium (DYS/SC), 39 squamous cell carcinoma (SCCA), 29 areas of Barrett's esophagus, 48 of Barrett's dysplasia (DYS/BAR) and 33 areas of adenocarcinoma (AC) [17].

Associations of IKBKAP with chemical compounds

  • Kinetin significantly increases inclusion of exon 20 from the endogenous gene, as well as from an IKBKAP minigene [18].
  • The reported ability of (-)-epigallocatechin gallate (EGCG), a polyphenol, to down-regulate the expression of hnRNP A2/B1, a trans-activating factor that encourages the use of intron-distal 5(') splice sites, prompted an evaluation of its effect on the IKBKAP transcript in FD-derived cells [19].
  • The most useful one (5' DYS MSA) has 10 alleles with a 57% heterozygosity and can be tested on small polyacrylamide gels in a nonradioactive PCR-based assay [20].
  • There is significant homology in the amino acid sequence of IKAP across species and the serine/threonine kinase phosphorylation site altered in the minor FD mutation of IKAP is conserved [21].
  • We report the ability of tocotrienols, members of the vitamin E family, to increase transcription of IKAP mRNA in FD-derived cells, with corresponding increases in the correctly spliced transcript and normal protein [22].

Physical interactions of IKBKAP

  • Rab7 is required for late endosomal transport and here we establish that the phosphatidylinositol 3'-kinase hVPS34 and its adaptor protein p150 are rab7 interacting partners [15].
  • These in silico predictions were corroborated using IKBKAP minigenes in a new rapid and simple in vitro coupled RNA polymerase (RNAP) II transcription/splicing assay [23].

Regulatory relationships of IKBKAP

  • Importantly, IKAP also enhanced JNK activation induced by ultraviolet light irradiation as well as treatments with tumor necrosis factor or epidermal growth factor [24].

Other interactions of IKBKAP

  • Using both densitometry and real-time quantitative polymerase chain reaction, we found that relative WT:MU IKBKAP RNA levels were highest in cultured patient lymphoblasts and lowest in postmortem central and peripheral nervous tissues [14].
  • We cloned IKAP as a JNK-associating protein using the Ras recruitment yeast two-hybrid system [24].
  • IKAP and IKK gamma belong to distinct cellular complexes [25].
  • Human VPS34 and p150 are Rab7 interacting partners [15].

Analytical, diagnostic and therapeutic context of IKBKAP

  • To test the possible role of SNPs in the coding region of the IKAP gene in atopic asthma or other atopic phenotypes in a highly homogenous Czech population, a case-control study including 373 patients and 309 healthy control subjects was performed [4].
  • Native immunoprecipitation experiments confirm that Sec13p exists in a complex with p150 in wild type cells [26].
  • Up to 75 mg FD and up to 37 mg Ba could be eliminated per treatment, depending on the plasma concentrations and the filtration volume [27].
  • To better understand the relationship between the genotype of FD patients and their phenotype, we have used in situ hybridization histochemistry to map the IKAP mRNA in sections of whole rat embryos [28].
  • We used dystrophin staining with monoclonal NCL-DYS (rod domain) antidystrophin antibody using the avidin-biotin conjugate immunoperoxidase technique in 16 out of 20 patients with various types of muscular dystrophies at a large tertiary care medical centre in India. RESULTS [29].


  1. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Slaugenhaupt, S.A., Blumenfeld, A., Gill, S.P., Leyne, M., Mull, J., Cuajungco, M.P., Liebert, C.B., Chadwick, B., Idelson, M., Reznik, L., Robbins, C., Makalowska, I., Brownstein, M., Krappmann, D., Scheidereit, C., Maayan, C., Axelrod, F.B., Gusella, J.F. Am. J. Hum. Genet. (2001) [Pubmed]
  2. Hereditary sensory neuropathies. Auer-Grumbach, M. Drugs of today (Barcelona, Spain : 1998) (2004) [Pubmed]
  3. Therapeutic potential and mechanism of kinetin as a treatment for the human splicing disease familial dysautonomia. Hims, M.M., Ibrahim, e.l. .C., Leyne, M., Mull, J., Liu, L., Lazaro, C., Shetty, R.S., Gill, S., Gusella, J.F., Reed, R., Slaugenhaupt, S.A. J. Mol. Med. (2007) [Pubmed]
  4. The role of the IKAP gene polymorphisms in atopic diseases in the middle European population. Schüller, M., Izakovicová Hollá, L., Bucková, D., Znojil, V., Stelcl, M., Rybnícek, O., Vácha, J. J. Hum. Genet. (2003) [Pubmed]
  5. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Maya, R., Balass, M., Kim, S.T., Shkedy, D., Leal, J.F., Shifman, O., Moas, M., Buschmann, T., Ronai, Z., Shiloh, Y., Kastan, M.B., Katzir, E., Oren, M. Genes Dev. (2001) [Pubmed]
  6. Comorbid depression and anxiety in fibromyalgia syndrome: relationship to somatic and psychosocial variables. Thieme, K., Turk, D.C., Flor, H. Psychosomatic medicine. (2004) [Pubmed]
  7. IKAP is a scaffold protein of the IkappaB kinase complex. Cohen, L., Henzel, W.J., Baeuerle, P.A. Nature (1998) [Pubmed]
  8. Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia. Close, P., Hawkes, N., Cornez, I., Creppe, C., Lambert, C.A., Rogister, B., Siebenlist, U., Merville, M.P., Slaugenhaupt, S.A., Bours, V., Svejstrup, J.Q., Chariot, A. Mol. Cell (2006) [Pubmed]
  9. Tubulin tyrosination is a major factor affecting the recruitment of CAP-Gly proteins at microtubule plus ends. Peris, L., Thery, M., Fauré, J., Saoudi, Y., Lafanechère, L., Chilton, J.K., Gordon-Weeks, P., Galjart, N., Bornens, M., Wordeman, L., Wehland, J., Andrieux, A., Job, D. J. Cell Biol. (2006) [Pubmed]
  10. The Chromatin Assembly Factor Subunit FASCIATA1 Is Involved in Homologous Recombination in Plants. Kirik, A., Pecinka, A., Wendeler, E., Reiss, B. Plant Cell (2006) [Pubmed]
  11. Genetics of familial dysautonomia. Tissue-specific expression of a splicing mutation in the IKBKAP gene. Slaugenhaupt, S.A. Clin. Auton. Res. (2002) [Pubmed]
  12. Identification of the first non-Jewish mutation in familial Dysautonomia. Leyne, M., Mull, J., Gill, S.P., Cuajungco, M.P., Oddoux, C., Blumenfeld, A., Maayan, C., Gusella, J.F., Axelrod, F.B., Slaugenhaupt, S.A. Am. J. Med. Genet. A (2003) [Pubmed]
  13. Familial dysautonomia is caused by mutations of the IKAP gene. Anderson, S.L., Coli, R., Daly, I.W., Kichula, E.A., Rork, M.J., Volpi, S.A., Ekstein, J., Rubin, B.Y. Am. J. Hum. Genet. (2001) [Pubmed]
  14. Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia. Cuajungco, M.P., Leyne, M., Mull, J., Gill, S.P., Lu, W., Zagzag, D., Axelrod, F.B., Maayan, C., Gusella, J.F., Slaugenhaupt, S.A. Am. J. Hum. Genet. (2003) [Pubmed]
  15. Human VPS34 and p150 are Rab7 interacting partners. Stein, M.P., Feng, Y., Cooper, K.L., Welford, A.M., Wandinger-Ness, A. Traffic (2003) [Pubmed]
  16. Identification of mouse hepatitis virus papain-like proteinase 2 activity. Kanjanahaluethai, A., Baker, S.C. J. Virol. (2000) [Pubmed]
  17. Esophagin and proliferating cell nuclear antigen (PCNA) are biomarkers of human esophageal neoplastic progression. Kimos, M.C., Wang, S., Borkowski, A., Yang, G.Y., Yang, C.S., Perry, K., Olaru, A., Deacu, E., Sterian, A., Cottrell, J., Papadimitriou, J., Sisodia, L., Selaru, F.M., Mori, Y., Xu, Y., Yin, J., Abraham, J.M., Meltzer, S.J. Int. J. Cancer (2004) [Pubmed]
  18. Rescue of a human mRNA splicing defect by the plant cytokinin kinetin. Slaugenhaupt, S.A., Mull, J., Leyne, M., Cuajungco, M.P., Gill, S.P., Hims, M.M., Quintero, F., Axelrod, F.B., Gusella, J.F. Hum. Mol. Genet. (2004) [Pubmed]
  19. EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with familial dysautonomia. Anderson, S.L., Qiu, J., Rubin, B.Y. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  20. Nonradioactive assay for new microsatellite polymorphisms at the 5' end of the dystrophin gene, and estimation of intragenic recombination. Oudet, C., Heilig, R., Hanauer, A., Mandel, J.L. Am. J. Hum. Genet. (1991) [Pubmed]
  21. Genomic organization and chromosomal localization of the mouse IKBKAP gene. Coli, R., Anderson, S.L., Volpi, S.A., Rubin, B.Y. Gene (2001) [Pubmed]
  22. Tocotrienols induce IKBKAP expression: a possible therapy for familial dysautonomia. Anderson, S.L., Qiu, J., Rubin, B.Y. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  23. Weak definition of IKBKAP exon 20 leads to aberrant splicing in familial dysautonomia. Ibrahim, e.l. .C., Hims, M.M., Shomron, N., Burge, C.B., Slaugenhaupt, S.A., Reed, R. Hum. Mutat. (2007) [Pubmed]
  24. A novel specific role for I kappa B kinase complex-associated protein in cytosolic stress signaling. Holmberg, C., Katz, S., Lerdrup, M., Herdegen, T., Jäättelä, M., Aronheim, A., Kallunki, T. J. Biol. Chem. (2002) [Pubmed]
  25. The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component. Krappmann, D., Hatada, E.N., Tegethoff, S., Li, J., Klippel, A., Giese, K., Baeuerle, P.A., Scheidereit, C. J. Biol. Chem. (2000) [Pubmed]
  26. The Sec13p complex and reconstitution of vesicle budding from the ER with purified cytosolic proteins. Salama, N.R., Yeung, T., Schekman, R.W. EMBO J. (1993) [Pubmed]
  27. Significant reduction of factor D and immunosuppressive complement fragment Ba by hemofiltration. Kaiser, J.P., Oppermann, M., Götze, O., Deppisch, R., Göhl, H., Asmus, G., Röhrich, B., von Herrath, D., Schaefer, K. Blood Purif. (1995) [Pubmed]
  28. Of splice and men: what does the distribution of IKAP mRNA in the rat tell us about the pathogenesis of familial dysautonomia? Mezey, E., Parmalee, A., Szalayova, I., Gill, S.P., Cuajungco, M.P., Leyne, M., Slaugenhaupt, S.A., Brownstein, M.J. Brain Res. (2003) [Pubmed]
  29. Dystrophin assay in muscular dystrophies: an Indian experience. Jain, S., Sarkar, C., Dinda, A.K., Maheshwari, M.C. The National medical journal of India. (1993) [Pubmed]
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