IKBKAP ( inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein ) is a human gene encoding the IKAP protein, which is ubiquitously expressed at varying levels in all tissue types, including brain cells. The IKAP protein is thought to participate as a sub-unit in the assembly of a six-protein putative human holo-Elongator complex, which allows for transcriptional elongation by RNA polymerase II . Further evidence has implicated the IKAP protein as being critical in neuronal development, and directs that decreased expression of IKAP in certain cell types is the molecular basis for the severe, neurodevelopmental disorder familial dysautonomia . Other pathways that have been connected to IKAP protein function in a variety of organisms include tRNA modification, cell motility, and cytosolic stress signalling. Homologs of the IKBKAP gene have been identified in multiple other Eukaryotic model organisms . Notable homologs include Elp1 in yeast , Ikbkap in mice, and D-elp1 in fruit flies . The fruit fly homolog (D-elp1) has RNA-dependent RNA polymerase activity and is involved in RNA interference .
22-540: The IKBKAP gene is located on the long (q) arm of chromosome 9 at position 31, from base pair 108,709,355 to base pair 108,775,950. Originally, it was proposed that the IKBKAP gene in humans was encoding a scaffolding protein (IKAP) for the IκB enzyme kinase (IKK) complex, which is involved in pro-inflammatory cytokine signal transduction in the NF-κB signalling pathway. However, this
44-405: A lower bound on the total number of human protein-coding genes. The following is a partial list of genes on human chromosome 9. For a complete list, see the link in the infobox on the right. The following diseases are some of those related to genes on chromosome 9: Wild type The wild type ( WT ) is the phenotype of the typical form of a species as it occurs in nature. Originally,
66-462: A population. Research involving the manipulation of wild-type alleles has application in many fields, including fighting disease and commercial food production. The genetic sequence for wild-type versus "mutant" phenotypes and how these genes interact in expression is the subject of much research. Better understanding of these processes is hoped to bring about methods for preventing and curing diseases that are currently incurable such as infection with
88-538: A possible future oral treatment. [REDACTED] This article incorporates public domain material from Genetics Home Reference . United States National Library of Medicine . Chromosome 9 (human) Chromosome 9 is one of the 23 pairs of chromosomes in humans . Humans normally have two copies of this chromosome, as they normally do with all chromosomes. Chromosome 9 spans about 138 million base pairs of nucleic acids (the building blocks of DNA ) and represents between 4.0 and 4.5% of
110-739: Is also being done to establish how viruses transition between species to identify harmful viruses with the potential to infect humans. Selective breeding to enhance the most beneficial traits is the structure upon which agriculture is built, this expedited the evolution process to make crop plants and animals larger and more disease resistant. Genetic manipulation went further. Genetic alteration of plants leads to not only larger crop production, but also more nutritious products, allowing isolated populations to receive vital vitamins and minerals that would otherwise be unavailable to them. Utilization of these wild-type mutations has also led to plants capable of growing in extremely arid environments, making more of
132-477: Is especially prevalent in the Ashkenazi Jewish population, where 1/3600 live births present familial dysautonomia. By 2001, the genetic cause of familial dysautonomia was localized to a dysfunctional region spanning 177kb on chromosome 9q31. With the use of blood samples from diagnosed patients, the implicated region was successfully sequenced . The IKBKAP gene, one of the five genes identified in that region,
154-452: Is now appreciated that most or all gene loci exist in a variety of allelic forms, which vary in frequency throughout the geographic range of a species, and that a uniform wild type does not exist. In general, however, the most prevalent allele – i.e., the one with the highest gene frequency – is the one deemed wild type. The concept of wild type is useful in some experimental organisms such as fruit flies Drosophila melanogaster , in which
176-416: Is removed from the pre-mRNA with the introns. The unintentional removal of an exon from the final mRNA product is termed exon skipping . Therefore, there is a decreased level of functional IKAP protein expression within affected tissue. However, this disorder is tissue-specific. Lymphoblasts , even with the mutation present, may continue to express some functional IKAP protein. In contrast, brain tissue with
198-456: Is replaced by proline at position 696 in the IKAP protein's chain of amino acids (also written as Arg696Pro), or proline is replaced by leucine at position 914 (also written as Pro914Leu). Together, these mutations cause the resulting IKAP protein to malfunction. As an autosomal recessive disorder , two mutated alleles of the IKBKAP gene are required for the disorder to manifest. However, despite
220-449: The application of stressors such as ultraviolet light and TNF-α (a pro-inflammatory cytokine). IKAP is now also widely acknowledged to have a role in transcriptional elongation in humans. The RNA polymerase II holoenzyme constitutes partly of a multi-subunit histone acetyltransferase element known as the RNA polymerase II elongator complex, of which IKAP is one subunit. The association of
242-447: The development of wild-type sensory and autonomic neurons are improperly transcribed. An extension of this research suggests that genes involved in cell migration are impaired in the nervous system, creating a foundation for this disorder. In a small number of reported familial dysautonomia cases, researchers have identified other mutations that cause a change in amino acids (the building blocks of proteins ). In these cases, arginine
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#1733104906823264-545: The elongator complex functioning in a variety of processes — from exocytosis to tRNA modification. This finding demonstrates that the function of the elongator complex is not conserved among species. Familial dysautonomia (also known as “Riley-Day syndrome”) is a complex congenital neurodevelopmental disease , characterized by unusually low numbers of neurons in the sensory and autonomic nervous systems . The resulting symptoms of patients include gastrointestinal dysfunction , scoliosis , and pain insensitivity . This disease
286-420: The elongator complex with RNA polymerase II holoenzyme is necessary for subsequent binding to nascent pre-mRNA of certain target genes, and thus their successful transcription . Specifically, within the cell, the depletion of functional elongater complexes due to low IKAP expression has been found to have a profound effect on transcription of genes involved in cell migration . In yeast, experimental data shows
308-479: The herpes virus. One example of such promising research in these fields was the study done examining the link between wild-type mutations and certain types of lung cancer. Research is also being done dealing with the manipulation of certain wild-type traits in viruses to develop new vaccines. This research may lead to new ways to combat deadly viruses such as the Ebola virus and HIV . Research using wild-type mutations
330-443: The planet habitable than ever before. As more is understood about these genes, agriculture will continue to become a more efficient process, which will be relied upon to sustain a continually growing population. Amplification of advantageous genes allows the best traits in a population to be present at much higher percentages than normal, although this practice has been the subject of some ethical debate . These changes have also been
352-404: The predominance of the same single-base mutation being the reputed cause of familial dysautonomia, the severity of the affected phenotype varies within and between families. Kinetin (6-furfurylaminopurine) has been found to have the capacity to repair the splicing defect and increase wild-type IKBKAP mRNA expression in vivo . Further research is still required to assess the fitness of kinetin as
374-408: The single-base mutation in the IKBKAP gene predominantly express a resulting truncated, mutant IKAP protein which is nonfunctional. The exact mechanism for how the familial dysautonomia phenotype is induced due to reduced IKAP expression is unclear; still, as a protein involved in transcriptional regulation, there have been a variety of proposed mechanisms. One such theory suggests that critical genes in
396-461: The standard phenotypes for features such as eye color or wing shape are known to be altered by particular mutations that produce distinctive phenotypes, such as "white eyes" or "vestigial wings". Wild-type alleles are indicated with a "+" superscript, for example w and vg for red eyes and full-size wings, respectively. Manipulation of the genes behind these traits led to the current understanding of how organisms form and how traits mutate within
418-450: The total DNA in cells . These are some of the gene count estimates of human chromosome 9. Because researchers use different approaches to genome annotation , their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction ). Among various projects, the collaborative consensus coding sequence project ( CCDS ) takes an extremely conservative strategy. So CCDS's gene number prediction represents
440-453: The wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, " mutant " allele. "Mutant" alleles can vary to a great extent, and even become the wild type if a genetic shift occurs within the population. Continued advancements in genetic mapping technologies have created a better understanding of how mutations occur and interact with other genes to alter phenotype. It
462-402: Was found to have a single-base mutation in over 99.5% of cases of familial dysautonomia seen. The single-base mutation, overwhelmingly noted as a transition from cytosine to thymine , is present in the 5’ splice donor site of intron 20 in the IKBKAP pre-mRNA. This prevents recruitment of splicing machinery , and thus exon 19 is spliced directly to exon 21 in the final mRNA product – exon 20
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#1733104906823484-542: Was subsequently disproven when researchers applied a gel filtration method and could not identify IKK complexes contained in fractions with IKAP, thus dissociating IKAP from having a role in the NF-κB signalling pathway. Later, it was discovered that IKAP functions as a cytoplasmic scaffold protein in the mammalian JNK-signalling pathway which is activated in response to stress stimuli. In an in vivo experiment, researchers showed direct interaction between IKAP and JNK induced by
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