Disease relevance of IKBKAP

• Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia [1].
• Autosomal-recessive hereditary sensory neuropathies types III and IV, and probably also type V, result from mutations in the IKBKAP and NTRK1 genes [2].
• Familial dysautonomia (FD) is a recessive neurodegenerative disease caused by a T to C transition at base pair 6 of IKBKAP intron 20 [3].
• Among a variety of other loci, specific variants of the gene for IKAP (IKK complex-associated protein) were shown to be associated with bronchial asthma in children in a Japanese study [4].
• Phage display analysis identified a consensus 2A10 recognition sequence, possessing the core motif DYS [5].

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

• Genetics of familial dysautonomia. Tissue-specific expression of a splicing mutation in the IKBKAP gene [11].
• In this report, we describe the first non-Jewish IKBKAP mutation, a proline to leucine missense mutation in exon 26, P914L [12].
• The defective gene DYS, which is responsible for familial dysautonomia (FD) and has been mapped to a 0.5-cM region on chromosome 9q31, has eluded identification [13].
• We identified and characterized the RNAs encoded by this region of chromosome 9 in cell lines derived from individuals homozygous for the major FD haplotype, and we observed that the RNA encoding the IkappaB kinase complex-associated protein (IKAP) lacks exon 20 and, as a result of a frameshift, encodes a truncated protein [13].
• This mutation results in defective phosphorylation of IKAP [13].

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].

References