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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.<ref>{{Cite web|url=https://www.researchgate.net/figure/11316176_fig3_FIG-3-IKAP-is-ubiquitously-expressed-A-IKAP-expression-in-various-adult-tissues|title=FIG. 3. IKAP is ubiquitously expressed . A, IKAP expression in various...|website=ResearchGate|language=en|access-date=2017-11-30}}</ref>  The IKAP protein is thought to participate as a sub-unit in the assembly of a six-protein putative human holo-Elongator complex,<ref>{{Cite journal|last=Mezey|first=Eva|last2=Parmalee|first2=Alissa|last3=Szalayova|first3=Ildiko|last4=Gill|first4=Sandra P.|last5=Cuajungco|first5=Math P.|last6=Leyne|first6=Maire|last7=Slaugenhaupt|first7=Susan A.|last8=Brownstein|first8=Michael J.|date=2003-09-05|title=Of splice and men: what does the distribution of IKAP mRNA in the rat tell us about the pathogenesis of familial dysautonomia?|journal=Brain Research|volume=983|issue=1-2|pages=209–214|issn=0006-8993|pmid=12914982}}</ref> 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|familial dysautonomy]].<ref name=":0">{{Cite journal|last=Slaugenhaupt|first=Susan A.|last2=Blumenfeld|first2=Anat|last3=Gill|first3=Sandra P.|last4=Leyne|first4=Maire|last5=Mull|first5=James|last6=Cuajungco|first6=Math P.|last7=Liebert|first7=Christopher B.|last8=Chadwick|first8=Brian|last9=Idelson|first9=Maria|date=2001-3|title=Tissue-Specific Expression of a Splicing Mutation in the IKBKAP Gene Causes Familial Dysautonomia|journal=American Journal of Human Genetics|volume=68|issue=3|pages=598–605|issn=0002-9297|pmc=1274473|pmid=11179008}}</ref>  Other pathways that have been connected to IKAP protein function in a variety of organisms include [[Transfer RNA|tRNA]] modification,<ref>{{Cite journal|date=2017-11-30|title=User:AnnaBasu/sandbox|url=https://en.wikipedia.org/w/index.php?title=User:AnnaBasu/sandbox&oldid=812931903|journal=Wikipedia|language=en}}</ref> cell motility,<ref name=":2"/> and cytosolic stress signalling.<ref name=":1"/>{{infobox protein
{{infobox protein
| Name = Inhibitor of κ light polypeptide gene enhancer in B-cells, kinase complex-associated protein
| Name = Inhibitor of κ light polypeptide gene enhancer in B-cells, kinase complex-associated protein
| caption =
| caption =
| image =
| image =
| width =
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| HGNCid = 1874
| HGNCid = 5959
| Symbol = IKBKAP
| Symbol = IKBKAP
| AltSymbols = FD, DYS, ELP1, IKAP, IKI3, TOT1, FLJ12497 and DKFZp781H1425
| AltSymbols = FD, DYS, ELP1, IKAP, IKI3, TOT1, FLJ12497 and DKFZp781H1425
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| LocusSupplementaryData =
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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.<ref name="Holmberg_2002" />  The IKAP protein is thought to participate as a sub-unit in the assembly of a six-protein putative human holo-Elongator complex,<ref>{{cite journal | vauthors = Mezey E, Parmalee A, Szalayova I, Gill SP, Cuajungco MP, Leyne M, Slaugenhaupt SA, Brownstein MJ | title = Of splice and men: what does the distribution of IKAP mRNA in the rat tell us about the pathogenesis of familial dysautonomia? | journal = Brain Research | volume = 983 | issue = 1–2 | pages = 209–14 | date = September 2003 | pmid = 12914982 | doi=10.1016/s0006-8993(03)03090-7}}</ref> 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|familial dysautonomy]].<ref name="Slaugenhaupt_2001" />  Other pathways that have been connected to IKAP protein function in a variety of organisms include [[Transfer RNA|tRNA]] modification,{{Citation needed|date=May 2018}} cell motility,<ref name="Close_2007" /> and cytosolic stress signalling.<ref name="Holmberg_2002" />
[[Homologs]] of the IKBKAP gene have been identified in multiple other Eukaryotic [[model organism]]s. Notable homologs include Elp1 in [[Saccharomyces cerevisiae|yeast]],<ref>{{cite journal | vauthors = Rahl PB, Chen CZ, Collins RN | title = Elp1p, the yeast homolog of the FD disease syndrome protein, negatively regulates exocytosis independently of transcriptional elongation | journal = Molecular Cell | volume = 17 | issue = 6 | pages = 841–53 | date = March 2005 | pmid = 15780940 | doi = 10.1016/j.molcel.2005.02.018 }}</ref> Ikbkap in mice,<ref>{{cite journal | vauthors = Cuajungco MP, Leyne M, Mull J, Gill SP, Gusella JF, Slaugenhaupt SA | title = Cloning, characterization, and genomic structure of the mouse Ikbkap gene | journal = DNA and Cell Biology | volume = 20 | issue = 9 | pages = 579–86 | date = September 2001 | pmid = 11747609 | doi = 10.1089/104454901317094990 }}</ref> and D-elp1 in [[Drosophila melanogaster|fruit flies]]. The fruit fly homolog (D-elp1) has [[RNA-dependent RNA polymerase]] activity and is involved in [[RNA interference]].<ref name="Lipardi_2009">{{cite journal | vauthors = Lipardi C, Paterson BM | title = Identification of an RNA-dependent RNA polymerase in Drosophila involved in RNAi and transposon suppression | language = en | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 37 | pages = 15645–50 | date = September 2009 | pmid = 19805217 | doi = 10.1073/pnas.0904984106 | pmc=2736140}}</ref>


[[Homologs]] of the IKBKAP gene have been identified in multiple other Eukaryotic [[model organism]]s. Notable homologs include Elp1 in [[Saccharomyces cerevisiae|yeast]],<ref>{{Cite journal|last=Rahl|first=Peter B.|last2=Chen|first2=Catherine Z.|last3=Collins|first3=Ruth N.|date=2005-03-18|title=Elp1p, the yeast homolog of the FD disease syndrome protein, negatively regulates exocytosis independently of transcriptional elongation|journal=Molecular Cell|volume=17|issue=6|pages=841–853|doi=10.1016/j.molcel.2005.02.018|issn=1097-2765|pmid=15780940}}</ref> Ikbkap in mice,<ref>{{Cite journal|last=Cuajungco|first=M. P.|last2=Leyne|first2=M.|last3=Mull|first3=J.|last4=Gill|first4=S. P.|last5=Gusella|first5=J. F.|last6=Slaugenhaupt|first6=S. A.|date=September 2001|title=Cloning, characterization, and genomic structure of the mouse Ikbkap gene|journal=DNA and cell biology|volume=20|issue=9|pages=579–586|doi=10.1089/104454901317094990|issn=1044-5498|pmid=11747609}}</ref> and D-elp1 in [[Drosophila melanogaster|fruit flies]]. The fruit fly homolog (D-elp1) has [[RNA-dependent RNA polymerase]] activity and is involved in [[RNA interference]].<ref name=":4">{{Cite journal|last=Lipardi|first=Concetta|last2=Paterson|first2=Bruce M.|date=2009-09-15|title=Identification of an RNA-dependent RNA polymerase in Drosophila involved in RNAi and transposon suppression|url=http://www.pnas.org/content/106/37/15645|journal=Proceedings of the National Academy of Sciences|language=en|volume=106|issue=37|pages=15645–15650|doi=10.1073/pnas.0904984106|issn=0027-8424|pmid=19805217}}</ref>
The IKBKAP gene is located on the long (q) arm of [[Chromosome 9 (human)|chromosome 9]] at position 31, from [[base pair]] 108,709,355 to base pair 108,775,950.
 
The IKBKAP gene is located on the long (q) arm of [[Chromosome 9 (human)|chromosome 9]] at position 31, from [[base pair]] 108,709,355 to base pair 108,775,950.


== Function and mechanism ==
== Function and mechanism ==
Originally, it was proposed that the IKBKAP gene in humans was encoding a [[Scaffold protein|scaffolding protein]] (IKAP) for the [[IκB kinase|IκB enzyme kinase]] (IKK) complex, which is involved in pro-inflammatory cytokine signal transduction in the [[NF-κB|NF-κB signalling pathway]].<ref>{{Cite journal|last=Baeuerle|first=Patrick A.|last2=Cohen|first2=Lucie|last3=Henzel|first3=William J.|date=1998/09|title=IKAP is a scaffold protein of the IκB kinase complex|url=https://www.nature.com/articles/26254|journal=Nature|language=En|volume=395|issue=6699|pages=292–296|doi=10.1038/26254|issn=1476-4687}}</ref> However, this was subsequently disproven when researchers applied a [[Size-exclusion chromatography|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.<ref>{{Cite journal|last=Krappmann|first=D.|last2=Hatada|first2=E. N.|last3=Tegethoff|first3=S.|last4=Li|first4=J.|last5=Klippel|first5=A.|last6=Giese|first6=K.|last7=Baeuerle|first7=P. A.|last8=Scheidereit|first8=C.|date=2000-09-22|title=The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component|journal=The Journal of Biological Chemistry|volume=275|issue=38|pages=29779–29787|doi=10.1074/jbc.M003902200|issn=0021-9258|pmid=10893415}}</ref>
Originally, it was proposed that the IKBKAP gene in humans was encoding a [[Scaffold protein|scaffolding protein]] (IKAP) for the [[IκB kinase|IκB enzyme kinase]] (IKK) complex, which is involved in pro-inflammatory cytokine signal transduction in the [[NF-κB]] signalling pathway.<ref>{{cite journal | vauthors = Cohen L, Henzel WJ, Baeuerle PA | title = IKAP is a scaffold protein of the IkappaB kinase complex | language = En | journal = Nature | volume = 395 | issue = 6699 | pages = 292–6 | date = September 1998 | pmid = 9751059 | doi = 10.1038/26254 }}</ref> However, this was subsequently disproven when researchers applied a [[Size-exclusion chromatography|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.<ref>{{cite journal | vauthors = Krappmann D, Hatada EN, Tegethoff S, Li J, Klippel A, Giese K, Baeuerle PA, Scheidereit C | title = The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component | journal = The Journal of Biological Chemistry | volume = 275 | issue = 38 | pages = 29779–87 | date = September 2000 | pmid = 10893415 | doi = 10.1074/jbc.M003902200 }}</ref>
[[File:Dimerization_of_Elp1.png|thumb|Dimerization of Elp1 is essential for Elongator complex assembly.]]
[[File:Dimerization of Elp1.png|thumb|Dimerization of Elp1 is essential for Elongator complex assembly.]]
Later, it was discovered that IKAP functions as a cytoplasmic scaffold protein in the mammalian [[C-Jun N-terminal kinases|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 the application of stressors such as [[Ultraviolet|ultraviolet light]] and [[TNF-α]] (a pro-inflammatory cytokine).<ref name=":1">{{Cite web|url=https://www.researchgate.net/publication/11316176_A_Novel_Specific_Role_for_IkB_Kinase_Complex-associated_Protein_in_Cytosolic_Stress_Signaling|title=A Novel Specific Role for IκB Kinase Complex-associated Protein in Cytosolic Stress Signaling (PDF Download Available)|website=ResearchGate|language=en|access-date=2017-11-30}}</ref>
Later, it was discovered that IKAP functions as a cytoplasmic scaffold protein in the mammalian [[C-Jun N-terminal kinases|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 the application of stressors such as [[ultraviolet]] light and [[TNF-α]] (a pro-inflammatory cytokine).<ref name="Holmberg_2002">{{cite journal | vauthors = Holmberg C, Katz S, Lerdrup M, Herdegen T, Jäättelä M, Aronheim A, Kallunki T | title = A novel specific role for I kappa B kinase complex-associated protein in cytosolic stress signaling | journal = The Journal of Biological Chemistry | volume = 277 | issue = 35 | pages = 31918–28 | year = 2002 | pmid = 12058026 | doi = 10.1074/jbc.M200719200 }}</ref>


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.<ref>{{Cite journal|last=Hawkes|first=Nicola A.|last2=Otero|first2=Gabriel|last3=Winkler|first3=G. Sebastiaan|last4=Marshall|first4=Nick|last5=Dahmus|first5=Michael E.|last6=Krappmann|first6=Daniel|last7=Scheidereit|first7=Claus|last8=Thomas|first8=Claire L.|last9=Schiavo|first9=Giampietro|date=2002-01-25|title=Purification and Characterization of the Human Elongator Complex|url=http://www.jbc.org/content/277/4/3047|journal=Journal of Biological Chemistry|language=en|volume=277|issue=4|pages=3047–3052|doi=10.1074/jbc.M110445200|issn=0021-9258|pmid=11714725}}</ref>  The association of the elongator complex with RNA polymerase II holoenzyme is necessary for subsequent binding to [[Pre-mRNA|nascent pre-mRNA]] of certain target genes, and thus their successful [[Transcription (biology)|transcription]].<ref>{{Cite journal|last=Xu|first=Huisha|last2=Lin|first2=Zhijie|last3=Li|first3=Fengzhi|last4=Diao|first4=Wentao|last5=Dong|first5=Chunming|last6=Zhou|first6=Hao|last7=Xie|first7=Xingqiao|last8=Wang|first8=Zheng|last9=Shen|first9=Yuequan|date=2015-08-25|title=Dimerization of elongator protein 1 is essential for Elongator complex assembly|url=http://www.pnas.org/content/112/34/10697|journal=Proceedings of the National Academy of Sciences|language=en|volume=112|issue=34|pages=10697–10702|doi=10.1073/pnas.1502597112|issn=0027-8424|pmid=26261306}}</ref> 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]].<ref>{{Cite journal|last=Close|first=Pierre|last2=Hawkes|first2=Nicola|last3=Cornez|first3=Isabelle|last4=Creppe|first4=Catherine|last5=Lambert|first5=Charles A.|last6=Rogister|first6=Bernard|last7=Siebenlist|first7=Ulrich|last8=Merville|first8=Marie-Paule|last9=Slaugenhaupt|first9=Susan A.|date=2006-05-19|title=Transcription Impairment and Cell Migration Defects in Elongator-Depleted Cells: Implication for Familial Dysautonomia|url=http://www.sciencedirect.com/science/article/pii/S1097276506002656|journal=Molecular Cell|volume=22|issue=4|pages=521–531|doi=10.1016/j.molcel.2006.04.017}}</ref>
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.<ref>{{cite journal | vauthors = Hawkes NA, Otero G, Winkler GS, Marshall N, Dahmus ME, Krappmann D, Scheidereit C, Thomas CL, Schiavo G, Erdjument-Bromage H, Tempst P, Svejstrup JQ | title = Purification and characterization of the human elongator complex | language = en | journal = The Journal of Biological Chemistry | volume = 277 | issue = 4 | pages = 3047–52 | date = January 2002 | pmid = 11714725 | doi = 10.1074/jbc.M110445200 }}</ref> The association of the elongator complex with RNA polymerase II holoenzyme is necessary for subsequent binding to [[Pre-mRNA|nascent pre-mRNA]] of certain target genes, and thus their successful [[Transcription (biology)|transcription]].<ref>{{cite journal | vauthors = Xu H, Lin Z, Li F, Diao W, Dong C, Zhou H, Xie X, Wang Z, Shen Y, Long J | title = Dimerization of elongator protein 1 is essential for Elongator complex assembly | language = en | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 34 | pages = 10697–702 | date = August 2015 | pmid = 26261306 | doi = 10.1073/pnas.1502597112 | pmc=4553795}}</ref> 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]].<ref>{{cite journal | vauthors = Close P, Hawkes N, Cornez I, Creppe C, Lambert CA, Rogister B, Siebenlist U, Merville MP, Slaugenhaupt SA, Bours V, Svejstrup JQ, Chariot A | title = Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia | journal = Molecular Cell | volume = 22 | issue = 4 | pages = 521–31 | date = May 2006 | pmid = 16713582 | doi = 10.1016/j.molcel.2006.04.017 }}</ref>


In yeast, experimental data shows the elongator complex functioning in a variety of processes —  from [[exocytosis]] to tRNA modification.<ref>{{Cite journal|last=HUANG|first=BO|last2=JOHANSSON|first2=MARCUS J.O.|last3=BYSTRÖM|first3=ANDERS S.|date=2005-4|title=An early step in wobble uridine tRNA modification requires the Elongator complex|journal=RNA|volume=11|issue=4|pages=424–436|doi=10.1261/rna.7247705|issn=1355-8382|pmc=1370732|pmid=15769872}}</ref> This finding demonstrates that the function of the elongator complex is not conserved among species.
In yeast, experimental data shows the elongator complex functioning in a variety of processes —  from [[exocytosis]] to tRNA modification.<ref>{{cite journal | vauthors = Huang B, Johansson MJ, Byström AS | title = An early step in wobble uridine tRNA modification requires the Elongator complex | journal = RNA | volume = 11 | issue = 4 | pages = 424–36 | date = April 2005 | pmid = 15769872 | pmc = 1370732 | doi = 10.1261/rna.7247705 }}</ref> This finding demonstrates that the function of the elongator complex is not conserved among species.


==Related conditions==
== Related conditions ==


=== Familial Dysautonomia ===
=== Familial Dysautonomia ===
Familial dysautonomia (also known as “Riley-Day syndrome”) is a complex congenital [[Neurodevelopmental disorder|neurodevelopmental disease]], characterized by unusually low numbers of neurons in the [[Sensory nervous system|sensory]] and [[autonomic nervous system]]s. The resulting symptoms of patients include [[Gastrointestinal disease|gastrointestinal dysfunction]], [[scoliosis]], and [[pain insensitivity]]. This disease is especially prevalent in the [[Ashkenazi Jews|Ashkenazi Jewish]] population, where 1/3600 live births present familial dysautonomia.<ref name=":0" />
Familial dysautonomia (also known as “Riley-Day syndrome”) is a complex congenital [[Neurodevelopmental disorder|neurodevelopmental disease]], characterized by unusually low numbers of neurons in the [[Sensory nervous system|sensory]] and [[autonomic nervous system]]s. The resulting symptoms of patients include [[Gastrointestinal disease|gastrointestinal dysfunction]], [[scoliosis]], and [[pain insensitivity]]. This disease is especially prevalent in the [[Ashkenazi Jews|Ashkenazi Jewish]] population, where 1/3600 live births present familial dysautonomia.<ref name="Slaugenhaupt_2001" />
 
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 [[DNA sequencing|sequenced]]. The IKBKAP gene, one of the five genes identified in that region, was found to have a single-base mutation in over 99.5% of cases of familial dysautonomia seen.<ref name="Slaugenhaupt_2001" />


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 [[DNA sequencing|sequenced]]. The IKBKAP gene, one of the five genes identified in that region, was found to have a single-base mutation in over 99.5% of cases of familial dysautonomia seen.<ref name=":0" />
The single-base mutation, overwhelmingly noted as a [[Transition (genetics)|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 [[Spliceosome|splicing machinery]], and thus exon 19 is spliced directly to exon 21 in the final mRNA product – exon 20 is removed from the pre-mRNA with the introns. The unintentional removal of an [[exon]] from the final mRNA product is termed [[exon skipping]].<ref name="Slaugenhaupt_2001" /> Therefore, there is a decreased level of functional IKAP protein expression within affected tissue. However, this disorder is tissue-specific. [[Lymphoblast]]s, even with the mutation present, may continue to express some functional IKAP protein. In contrast, brain tissue with the single-base mutation in the IKBKAP gene predominantly express a resulting truncated, mutant IKAP protein which is nonfunctional.<ref name="Slaugenhaupt_2001" /> 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 the development of [[Wild type|wild-type]] sensory and autonomic neurons are improperly transcribed.<ref name="Slaugenhaupt_2001" /> An extension of this research suggests that genes involved in cell migration are impaired in the nervous system, creating a foundation for this disorder.<ref name="Close_2007">{{cite journal | vauthors = Close P, Creppe C, Cornez I, Chariot MA, Chariot A | title = [Molecular and cellular characterization ion of IKAP protein and the Elongator complex. Implications for familial dysautonomia] | journal = Bulletin Et Memoires De l'Academie Royale De Medecine De Belgique | volume = 162 | issue = 5–6 | pages = 315–22 | date = 2007 | pmid = 18405001 }}</ref>


The single-base mutation, overwhelmingly noted as a [[Transition (genetics)|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 [[Spliceosome|splicing machinery]], and thus exon 19 is spliced directly to exon 21 in the final mRNA product – exon 20 is removed from the pre-mRNA with the introns. The unintentional removal of an [[exon]] from the final mRNA product is termed [[exon skipping]].<ref name=":0" /> Therefore, there is a decreased level of functional IKAP protein expression within affected tissue. However, this disorder is tissue-specific. [[Lymphoblast]]s, even with the mutation present, may continue to express some functional IKAP protein. In contrast, brain tissue with the single-base mutation in the IKBKAP gene predominantly express a resulting truncated, mutant IKAP protein which is nonfunctional.<ref name=":0" /> 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 the development of [[Wild type|wild-type]] sensory and autonomic neurons are improperly transcribed.<ref name=":0" /> An extension of this research suggests that genes involved in cell migration are impaired in the nervous system, creating a foundation for this disorder.<ref name=":2">{{Cite journal|last=Close|first=P.|last2=Creppe|first2=C.|last3=Cornez|first3=I.|last4=Chariot|first4=M. A.|last5=Chariot|first5=A.|date=2007|title=[Molecular and cellular characterization ion of IKAP protein and the Elongator complex. Implications for familial dysautonomia]|journal=Bulletin Et Memoires De l'Academie Royale De Medecine De Belgique|volume=162|issue=5-6|pages=315–322|issn=0377-8231|pmid=18405001}}</ref>
In a small number of reported familial dysautonomia cases, researchers have identified other mutations that cause a change in [[amino acid]]s (the building blocks of [[protein]]s). In these cases, [[arginine]] 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.<ref>{{cite journal | vauthors = Anderson SL, Coli R, Daly IW, Kichula EA, Rork MJ, Volpi SA, Ekstein J, Rubin BY | title = Familial dysautonomia is caused by mutations of the IKAP gene | journal = American Journal of Human Genetics | volume = 68 | issue = 3 | pages = 753–8 | date = March 2001 | pmid = 11179021 | pmc = 1274486 | doi = 10.1086/318808 }}</ref>


In a small number of reported familial dysautonomia cases, researchers have identified other mutations that cause a change in [[amino acid]]s (the building blocks of [[protein]]s). In these cases, [[arginine]] 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.<ref>{{Cite journal|last=Anderson|first=Sylvia L.|last2=Coli|first2=Rocco|last3=Daly|first3=Ira W.|last4=Kichula|first4=Elizabeth A.|last5=Rork|first5=Matthew J.|last6=Volpi|first6=Sabrina A.|last7=Ekstein|first7=Josef|last8=Rubin|first8=Berish Y.|date=2001-3|title=Familial Dysautonomia Is Caused by Mutations of the IKAP Gene|journal=American Journal of Human Genetics|volume=68|issue=3|pages=753–758|issn=0002-9297|pmc=1274486|pmid=11179021}}</ref>
As an [[autosomal recessive disorder]], two mutated alleles of the IKBKAP gene are required for the disorder to manifest. However, despite 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.<ref name="Slaugenhaupt_2001" />


As an [[autosomal recessive disorder]], two mutated alleles of the IKBKAP gene are required for the disorder to manifest. However, despite 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.<ref name=":0" />
[[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 a possible future oral treatment.<ref>{{cite journal | vauthors = Axelrod FB, Liebes L, Gold-Von Simson G, Mendoza S, Mull J, Leyne M, Norcliffe-Kaufmann L, Kaufmann H, Slaugenhaupt SA | title = Kinetin improves IKBKAP mRNA splicing in patients with familial dysautonomia | journal = Pediatric Research | volume = 70 | issue = 5 | pages = 480–3 | date = November 2011 | pmid = 21775922 | pmc = 3189334 | doi = 10.1203/PDR.0b013e31822e1825 }}</ref>


[[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 a possible future oral treatment.<ref>{{Cite journal|last=Axelrod|first=Felicia B.|last2=Liebes|first2=Leonard|last3=Gold-von Simson|first3=Gabrielle|last4=Mendoza|first4=Sandra|last5=Mull|first5=James|last6=Leyne|first6=Maire|last7=Norcliffe-Kaufmann|first7=Lucy|last8=Kaufmann|first8=Horacio|last9=Slaugenhaupt|first9=Susan A.|date=2011-11|title=Kinetin improves IKBKAP mRNA splicing in patients with familial dysautonomia|journal=Pediatric research|volume=70|issue=5|pages=480–483|doi=10.1203/PDR.0b013e31822e1825|issn=0031-3998|pmc=3189334|pmid=21775922}}</ref>
== Model organisms ==


==Model organisms==
{| class="wikitable sortable collapsible collapsed" border="1" cellpadding="2" style="float: right;" |
{| class="wikitable sortable collapsible collapsed" border="1" cellpadding="2" style="float: right;" |
|+ ''Ikbkap'' knockout mouse phenotype
|+ ''Ikbkap'' knockout mouse phenotype
Line 109: Line 110:


=== Mouse ===
=== Mouse ===
A conditional [[knockout mouse]] line, called ''Ikbkap<sup>tm1a(KOMP)Wtsi</sup>''<ref name="allele_ref">{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Ikbkap |title=International Knockout Mouse Consortium}}</ref><ref name="mgi_allele_ref">{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4362242 |title=Mouse Genome Informatics}}</ref> was generated as part of the [[International Knockout Mouse Consortium]] program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the [[Wellcome Trust Sanger Institute]].<ref name="pmid21677750">{{Cite journal
A conditional [[knockout mouse]] line, called ''Ikbkap<sup>tm1a(KOMP)Wtsi</sup>''<ref name="allele_ref">{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Ikbkap |title=International Knockout Mouse Consortium}}</ref><ref name="mgi_allele_ref">{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4362242 |title=Mouse Genome Informatics}}</ref> was generated as part of the [[International Knockout Mouse Consortium]] program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the [[Wellcome Trust Sanger Institute]].<ref name="pmid21677750">{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = June 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = June 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = January 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}</ref>
| last1 = Skarnes |first1 =W. C.
| doi = 10.1038/nature10163
| last2 = Rosen | first2 = B.
| last3 = West | first3 = A. P.
| last4 = Koutsourakis | first4 = M.
| last5 = Bushell | first5 = W.
| last6 = Iyer | first6 = V.
| last7 = Mujica | first7 = A. O.
| last8 = Thomas | first8 = M.
| last9 = Harrow | first9 = J.
| last10 = Cox | first10 = T.
| last11 = Jackson | first11 = D.
| last12 = Severin | first12 = J.
| last13 = Biggs | first13 = P.
| last14 = Fu | first14 = J.
| last15 = Nefedov | first15 = M.
| last16 = De Jong | first16 = P. J.
| last17 = Stewart | first17 = A. F.
| last18 = Bradley | first18 = A.
| title = A conditional knockout resource for the genome-wide study of mouse gene function  
| journal = Nature  
| volume = 474  
| issue = 7351  
| pages = 337–342
| year = 2011  
| pmid = 21677750  
| pmc =3572410  
}}</ref><ref name="mouse_library">{{cite journal |author=Dolgin E |title=Mouse library set to be knockout |journal=Nature |volume=474 |issue=7351 |pages=262–3 |date=June 2011 |pmid=21677718 |doi=10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal |vauthors=Collins FS, Rossant J, Wurst W |title=A mouse for all reasons |journal=Cell |volume=128 |issue=1 |pages=9–13 |date=January 2007 |pmid=17218247 |doi=10.1016/j.cell.2006.12.018 }}</ref>


Male and female animals underwent a standardized [[phenotypic screen]] to determine the effects of deletion.<ref name="mgp_reference" /><ref name="pmid21722353">{{cite journal|vauthors=van der Weyden L, White JK, Adams DJ, Logan DW | title=The mouse genetics toolkit: revealing function and mechanism. | journal=Genome Biol | year= 2011 | volume= 12 | issue= 6 | pages= 224 | pmid=21722353 | doi=10.1186/gb-2011-12-6-224 | pmc=3218837}}</ref> Twenty five tests were carried out and two [[phenotypes]] were reported. No [[homozygous]] [[mutant]] embryos were identified during gestation, and in a separate study, none survived until [[weaning]]. The remaining tests were carried out on [[heterozygous]] mutant adult mice; no significant abnormalities were observed in these animals.<ref name="mgp_reference" />
Male and female animals underwent a standardized [[phenotypic screen]] to determine the effects of deletion.<ref name="mgp_reference" /><ref name="pmid21722353">{{cite journal | vauthors = van der Weyden L, White JK, Adams DJ, Logan DW | title = The mouse genetics toolkit: revealing function and mechanism | journal = Genome Biology | volume = 12 | issue = 6 | pages = 224 | date = June 2011 | pmid = 21722353 | pmc = 3218837 | doi = 10.1186/gb-2011-12-6-224 }}</ref> Twenty five tests were carried out and two [[phenotypes]] were reported. No [[homozygous]] [[mutant]] embryos were identified during gestation, and in a separate study, none survived until [[weaning]]. The remaining tests were carried out on [[heterozygous]] mutant adult mice; no significant abnormalities were observed in these animals.<ref name="mgp_reference" />


=== ''Saccharomyces cerevisiae'' ===
=== ''Saccharomyces cerevisiae'' ===
The homologous protein for IKAP in yeast is Elp1, with 29% identity and 46% similarity detected between the proteins. The yeast Elp1 protein is a subunit of a three-protein RNA polymerase II-associated elongator complex.<ref name=":3">{{Cite journal|last=Slaugenhaupt|first=Susan A.|last2=Blumenfeld|first2=Anat|last3=Gill|first3=Sandra P.|last4=Leyne|first4=Maire|last5=Mull|first5=James|last6=Cuajungco|first6=Math P.|last7=Liebert|first7=Christopher B.|last8=Chadwick|first8=Brian|last9=Idelson|first9=Maria|date=2001-03-01|title=Tissue-Specific Expression of a Splicing Mutation in the IKBKAP Gene Causes Familial Dysautonomia|url=http://www.sciencedirect.com/science/article/pii/S0002929707631000|journal=The American Journal of Human Genetics|volume=68|issue=3|pages=598–605|doi=10.1086/318810}}</ref>
The homologous protein for IKAP in yeast is Elp1, with 29% identity and 46% similarity detected between the proteins. The yeast Elp1 protein is a subunit of a three-protein RNA polymerase II-associated elongator complex.<ref name="Slaugenhaupt_2001">{{cite journal | vauthors = Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungco MP, Liebert CB, Chadwick B, Idelson M, Reznik L, Robbins C, Makalowska I, Brownstein M, Krappmann D, Scheidereit C, Maayan C, Axelrod FB, Gusella JF | title = Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia | journal = American Journal of Human Genetics | volume = 68 | issue = 3 | pages = 598–605 | year = 2001 | pmid = 11179008 | pmc = 1274473 | doi = 10.1086/318810 }}</ref>


=== ''Drosophila melanogaster'' ===
=== ''Drosophila melanogaster'' ===
The IKBKAP gene homolog in fruit flies is the CG10535 gene, encoding the D-elp1 protein — the largest of three subunits making the RNA polymerase II core elongator complex. <ref name=":0" /> This subunit was found to have RNA-dependent RNA polymerase activity, through which it could synthesize double-stranded RNA from single-stranded RNA templates. This activity was observed in a D-elp1 protein-dependent step converting transposon RNA into double-stranded RNA for processing by Dcr-2 (a ''Drosophila'' [[dicer]]), involved in further RNA degradation and silencing.<ref name=":4" />
The IKBKAP gene homolog in fruit flies is the CG10535 gene, encoding the D-elp1 protein — the largest of three subunits making the RNA polymerase II core elongator complex.<ref name="Slaugenhaupt_2001" /> This subunit was found to have RNA-dependent RNA polymerase activity, through which it could synthesize double-stranded RNA from single-stranded RNA templates. This activity was observed in a D-elp1 protein-dependent step converting transposon RNA into double-stranded RNA for processing by Dcr-2 (a ''Drosophila'' [[dicer]]), involved in further RNA degradation and silencing.<ref name="Lipardi_2009" />


==See also==
== See also ==
* [[Familial dysautonomia]]
* [[Familial dysautonomia]]


==References==
== References ==
{{Reflist}}
{{Reflist|33em}}


==Further reading==
== Further reading ==
* {{cite journal |vauthors=Anderson SL, Coli R, Daly IW, Kichula EA, Rork MJ, Volpi SA, Ekstein J, Rubin BY | title=Familial Dysautonomia Is Caused by Mutations of the IKAP Gene | journal=Am J Hum Genet | year=2001 | pages=753–8 | volume=68 | issue=3  | pmid=11179021 | doi=10.1086/318808 | pmc=1274486}}
{{refbegin|33em}}
* {{cite journal | author=Axelrod FB | title=Familial dysautonomia | journal=Muscle Nerve | year=2004 | pages=352–63 | volume=29 | issue=3  | pmid=14981733 | doi=10.1002/mus.10499}}
* {{cite journal | vauthors = Anderson SL, Coli R, Daly IW, Kichula EA, Rork MJ, Volpi SA, Ekstein J, Rubin BY | title = Familial dysautonomia is caused by mutations of the IKAP gene | journal = American Journal of Human Genetics | volume = 68 | issue = 3 | pages = 753–8 | date = March 2001 | pmid = 11179021 | pmc = 1274486 | doi = 10.1086/318808 }}
* {{cite journal |vauthors=Cuajungco MP, Leyne M, Mull J, Gill SP, Lu W, Zagzag D, Axelrod FB, Maayan C, Gusella JF, Slaugenhaupt SA | title=Tissue-Specific Reduction in Splicing Efficiency of IKBKAP Due to the Major Mutation Associated with Familial Dysautonomia | journal=Am J Hum Genet | year=2003 | pages=749–58 | volume=72 | issue=3  | pmid=12577200 | doi=10.1086/368263 | pmc=1180251}} ''[http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=12577200 Full text]''
* {{cite journal | vauthors = Axelrod FB | title = Familial dysautonomia | journal = Muscle & Nerve | volume = 29 | issue = 3 | pages = 352–63 | date = March 2004 | pmid = 14981733 | doi = 10.1002/mus.10499 }}
* {{cite journal |vauthors=Leyne M, Mull J, Gill SP, Cuajungco MP, Oddoux C, Blumenfeld A, Maayan C, Gusella JF, Axelrod FB, Slaugenhaupt SA | title=Identification of the first non-Jewish mutation in familial Dysautonomia | journal=Am J Med Genet A | year=2003 | pages=305–8 | volume=118 | issue=4  | pmid=12687659 | doi=10.1002/ajmg.a.20052}}
* {{cite journal | vauthors = Cuajungco MP, Leyne M, Mull J, Gill SP, Lu W, Zagzag D, Axelrod FB, Maayan C, Gusella JF, Slaugenhaupt SA | title = Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia | journal = American Journal of Human Genetics | volume = 72 | issue = 3 | pages = 749–58 | date = March 2003 | pmid = 12577200 | pmc = 1180251 | doi = 10.1086/368263 }} ''[http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=12577200 Full text]''
* {{cite journal |vauthors=Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungco MP, Liebert CB, Chadwick B, Idelson M, Reznik L, Robbins C, Makalowska I, Brownstein M, Krappmann D, Scheidereit C, Maayan C, Axelrod FB, Gusella JF | title=Tissue-Specific Expression of a Splicing Mutation in the IKBKAP Gene Causes Familial Dysautonomia | journal=Am J Hum Genet | year=2001 | pages=598–605 | volume=68 | issue=3 | pmid=11179008 | doi=10.1086/318810 | pmc=1274473}}
* {{cite journal | vauthors = Leyne M, Mull J, Gill SP, Cuajungco MP, Oddoux C, Blumenfeld A, Maayan C, Gusella JF, Axelrod FB, Slaugenhaupt SA | title = Identification of the first non-Jewish mutation in familial Dysautonomia | journal = American Journal of Medical Genetics. Part A | volume = 118A | issue = 4 | pages = 305–8 | date = May 2003 | pmid = 12687659 | doi = 10.1002/ajmg.a.20052 }}
* {{cite journal |vauthors=Slaugenhaupt SA, Gusella JF | title=Familial dysautonomia | journal=Curr Opin Genet Dev | year=2002 | pages=307–11 | volume=12 | issue=3  | pmid=12076674 | doi=10.1016/S0959-437X(02)00303-9}}
* {{cite journal | vauthors = Slaugenhaupt SA, Gusella JF | title = Familial dysautonomia | journal = Current Opinion in Genetics & Development | volume = 12 | issue = 3 | pages = 307–11 | date = June 2002 | pmid = 12076674 | doi = 10.1016/S0959-437X(02)00303-9 }}
{{refend}}
{{GHR}}
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[[Category:Human genes]]
[[Category:Genes mutated in mice]]
[[Category:Genes mutated in mice]]
[[Category:EC 2.7.11]]
[[Category:EC 2.7.11]]

Revision as of 01:50, 25 September 2018

Inhibitor of κ light polypeptide gene enhancer in B-cells, kinase complex-associated protein
Identifiers
SymbolIKBKAP
Alt. symbolsFD, DYS, ELP1, IKAP, IKI3, TOT1, FLJ12497 and DKFZp781H1425
Entrez8518
HUGO5959
OMIM603722
RefSeqNM_003640
UniProtO95163
Other data
LocusChr. 9 q13

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.[1] The IKAP protein is thought to participate as a sub-unit in the assembly of a six-protein putative human holo-Elongator complex,[2] 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 dysautonomy.[3] Other pathways that have been connected to IKAP protein function in a variety of organisms include tRNA modification,[citation needed] cell motility,[4] and cytosolic stress signalling.[1] Homologs of the IKBKAP gene have been identified in multiple other Eukaryotic model organisms. Notable homologs include Elp1 in yeast,[5] Ikbkap in mice,[6] and D-elp1 in fruit flies. The fruit fly homolog (D-elp1) has RNA-dependent RNA polymerase activity and is involved in RNA interference.[7]

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.

Function and mechanism

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.[8] However, this 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.[9]

File:Dimerization of Elp1.png
Dimerization of Elp1 is essential for Elongator complex assembly.

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 the application of stressors such as ultraviolet light and TNF-α (a pro-inflammatory cytokine).[1]

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.[10] The association of 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.[11] 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.[12]

In yeast, experimental data shows the elongator complex functioning in a variety of processes — from exocytosis to tRNA modification.[13] This finding demonstrates that the function of the elongator complex is not conserved among species.

Related conditions

Familial Dysautonomia

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 is especially prevalent in the Ashkenazi Jewish population, where 1/3600 live births present familial dysautonomia.[3]

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, was found to have a single-base mutation in over 99.5% of cases of familial dysautonomia seen.[3]

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 is removed from the pre-mRNA with the introns. The unintentional removal of an exon from the final mRNA product is termed exon skipping.[3] 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 the single-base mutation in the IKBKAP gene predominantly express a resulting truncated, mutant IKAP protein which is nonfunctional.[3] 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 the development of wild-type sensory and autonomic neurons are improperly transcribed.[3] An extension of this research suggests that genes involved in cell migration are impaired in the nervous system, creating a foundation for this disorder.[4]

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 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.[14]

As an autosomal recessive disorder, two mutated alleles of the IKBKAP gene are required for the disorder to manifest. However, despite 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.[3]

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 a possible future oral treatment.[15]

Model organisms

Model organisms have been used in the study of IKBKAP gene function.

Mouse

A conditional knockout mouse line, called Ikbkaptm1a(KOMP)Wtsi[19][20] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[21][22][23]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[17][24] Twenty five tests were carried out and two phenotypes were reported. No homozygous mutant embryos were identified during gestation, and in a separate study, none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals.[17]

Saccharomyces cerevisiae

The homologous protein for IKAP in yeast is Elp1, with 29% identity and 46% similarity detected between the proteins. The yeast Elp1 protein is a subunit of a three-protein RNA polymerase II-associated elongator complex.[3]

Drosophila melanogaster

The IKBKAP gene homolog in fruit flies is the CG10535 gene, encoding the D-elp1 protein — the largest of three subunits making the RNA polymerase II core elongator complex.[3] This subunit was found to have RNA-dependent RNA polymerase activity, through which it could synthesize double-stranded RNA from single-stranded RNA templates. This activity was observed in a D-elp1 protein-dependent step converting transposon RNA into double-stranded RNA for processing by Dcr-2 (a Drosophila dicer), involved in further RNA degradation and silencing.[7]

See also

References

  1. ↑ 1.0 1.1 1.2 Holmberg C, Katz S, Lerdrup M, Herdegen T, Jäättelä M, Aronheim A, Kallunki T (2002). "A novel specific role for I kappa B kinase complex-associated protein in cytosolic stress signaling". The Journal of Biological Chemistry. 277 (35): 31918–28. doi:10.1074/jbc.M200719200. PMID 12058026.
  2. ↑ Mezey E, Parmalee A, Szalayova I, Gill SP, Cuajungco MP, Leyne M, Slaugenhaupt SA, Brownstein MJ (September 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. 983 (1–2): 209–14. doi:10.1016/s0006-8993(03)03090-7. PMID 12914982.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungco MP, Liebert CB, Chadwick B, Idelson M, Reznik L, Robbins C, Makalowska I, Brownstein M, Krappmann D, Scheidereit C, Maayan C, Axelrod FB, Gusella JF (2001). "Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia". American Journal of Human Genetics. 68 (3): 598–605. doi:10.1086/318810. PMC 1274473. PMID 11179008.
  4. ↑ 4.0 4.1 Close P, Creppe C, Cornez I, Chariot MA, Chariot A (2007). "[Molecular and cellular characterization ion of IKAP protein and the Elongator complex. Implications for familial dysautonomia]". Bulletin Et Memoires De l'Academie Royale De Medecine De Belgique. 162 (5–6): 315–22. PMID 18405001.
  5. ↑ Rahl PB, Chen CZ, Collins RN (March 2005). "Elp1p, the yeast homolog of the FD disease syndrome protein, negatively regulates exocytosis independently of transcriptional elongation". Molecular Cell. 17 (6): 841–53. doi:10.1016/j.molcel.2005.02.018. PMID 15780940.
  6. ↑ Cuajungco MP, Leyne M, Mull J, Gill SP, Gusella JF, Slaugenhaupt SA (September 2001). "Cloning, characterization, and genomic structure of the mouse Ikbkap gene". DNA and Cell Biology. 20 (9): 579–86. doi:10.1089/104454901317094990. PMID 11747609.
  7. ↑ 7.0 7.1 Lipardi C, Paterson BM (September 2009). "Identification of an RNA-dependent RNA polymerase in Drosophila involved in RNAi and transposon suppression". Proceedings of the National Academy of Sciences of the United States of America. 106 (37): 15645–50. doi:10.1073/pnas.0904984106. PMC 2736140. PMID 19805217.
  8. ↑ Cohen L, Henzel WJ, Baeuerle PA (September 1998). "IKAP is a scaffold protein of the IkappaB kinase complex". Nature. 395 (6699): 292–6. doi:10.1038/26254. PMID 9751059.
  9. ↑ Krappmann D, Hatada EN, Tegethoff S, Li J, Klippel A, Giese K, Baeuerle PA, Scheidereit C (September 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. 275 (38): 29779–87. doi:10.1074/jbc.M003902200. PMID 10893415.
  10. ↑ Hawkes NA, Otero G, Winkler GS, Marshall N, Dahmus ME, Krappmann D, Scheidereit C, Thomas CL, Schiavo G, Erdjument-Bromage H, Tempst P, Svejstrup JQ (January 2002). "Purification and characterization of the human elongator complex". The Journal of Biological Chemistry. 277 (4): 3047–52. doi:10.1074/jbc.M110445200. PMID 11714725.
  11. ↑ Xu H, Lin Z, Li F, Diao W, Dong C, Zhou H, Xie X, Wang Z, Shen Y, Long J (August 2015). "Dimerization of elongator protein 1 is essential for Elongator complex assembly". Proceedings of the National Academy of Sciences of the United States of America. 112 (34): 10697–702. doi:10.1073/pnas.1502597112. PMC 4553795. PMID 26261306.
  12. ↑ Close P, Hawkes N, Cornez I, Creppe C, Lambert CA, Rogister B, Siebenlist U, Merville MP, Slaugenhaupt SA, Bours V, Svejstrup JQ, Chariot A (May 2006). "Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia". Molecular Cell. 22 (4): 521–31. doi:10.1016/j.molcel.2006.04.017. PMID 16713582.
  13. ↑ Huang B, Johansson MJ, Byström AS (April 2005). "An early step in wobble uridine tRNA modification requires the Elongator complex". RNA. 11 (4): 424–36. doi:10.1261/rna.7247705. PMC 1370732. PMID 15769872.
  14. ↑ Anderson SL, Coli R, Daly IW, Kichula EA, Rork MJ, Volpi SA, Ekstein J, Rubin BY (March 2001). "Familial dysautonomia is caused by mutations of the IKAP gene". American Journal of Human Genetics. 68 (3): 753–8. doi:10.1086/318808. PMC 1274486. PMID 11179021.
  15. ↑ Axelrod FB, Liebes L, Gold-Von Simson G, Mendoza S, Mull J, Leyne M, Norcliffe-Kaufmann L, Kaufmann H, Slaugenhaupt SA (November 2011). "Kinetin improves IKBKAP mRNA splicing in patients with familial dysautonomia". Pediatric Research. 70 (5): 480–3. doi:10.1203/PDR.0b013e31822e1825. PMC 3189334. PMID 21775922.
  16. ↑ "Citrobacter infection data for Ikbkap". Wellcome Trust Sanger Institute.
  17. ↑ 17.0 17.1 17.2 Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88 (S248). doi:10.1111/j.1755-3768.2010.4142.x.
  18. ↑ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  19. ↑ "International Knockout Mouse Consortium".
  20. ↑ "Mouse Genome Informatics".
  21. ↑ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (June 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  22. ↑ Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  23. ↑ Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  24. ↑ van der Weyden L, White JK, Adams DJ, Logan DW (June 2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.

Further reading

 This article incorporates public domain material from the United States National Library of Medicine document "Genetics Home Reference".


External links

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