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{{Infobox_gene}}
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The '''huntingtin''' [[gene]], also called the '''HTT''' or '''HD''' (Huntington disease) gene, is the ''IT15'' ("interesting transcript 15") gene, which codes for a [[protein]] called the '''huntingtin protein'''.<ref name="pmid8458085">{{cite journal |author=The Huntington's Disease Collaborative Research Group | title = A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group | journal = Cell | volume = 72 | issue = 6 | pages = 971–83 | date = Mar 1993 | pmid = 8458085 | doi = 10.1016/0092-8674(93)90585-E }}</ref> The gene and its product are under heavy investigation as part of [[Huntington's disease]] clinical research and the suggested role for huntingtin in long-term memory storage.<ref>{{cite journal | vauthors = Choi YB, Kadakkuzha BM, Liu XA, Akhmedov K, Kandel ER, Puthanveettil SV | title = Huntingtin is critical both pre- and postsynaptically for long-term learning-related synaptic plasticity in Aplysia | journal = PLOS ONE | volume = 9 | issue = 7 | pages = e103004 | date = July 23, 2014 | pmid = 25054562 | doi = 10.1371/journal.pone.0103004 | pmc=4108396}}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = Huntingtin (Huntington disease)
| HGNCid = 4851
| Symbol = HD
| AltSymbols =; HTT; IT15
| OMIM = 143100
| ECnumber = 
| Homologene = 1593
| MGIid = 96067
| GeneAtlas_image1 = PBB_GE_HD_202389_s_at_tn.png
| Function = {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0003707 |text = steroid hormone receptor activity}} {{GNF_GO|id=GO:0003714 |text = transcription corepressor activity}} {{GNF_GO|id=GO:0005215 |text = transporter activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0008017 |text = microtubule binding}}
| Component = {{GNF_GO|id=GO:0005625 |text = soluble fraction}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005794 |text = Golgi apparatus}}
| Process = {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006915 |text = apoptosis}} {{GNF_GO|id=GO:0006917 |text = induction of apoptosis}} {{GNF_GO|id=GO:0007610 |text = behavior}} {{GNF_GO|id=GO:0009405 |text = pathogenesis}} {{GNF_GO|id=GO:0009887 |text = organ morphogenesis}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 3064
    | Hs_Ensembl = ENSG00000197386
    | Hs_RefseqProtein = NP_002102
    | Hs_RefseqmRNA = NM_002111
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 4
    | Hs_GenLoc_start = 3046206
    | Hs_GenLoc_end = 3215484
    | Hs_Uniprot = P42858
    | Mm_EntrezGene = 15194
    | Mm_Ensembl = ENSMUSG00000029104
    | Mm_RefseqmRNA = NM_010414
    | Mm_RefseqProtein = NP_034544
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 5
    | Mm_GenLoc_start = 35078597
    | Mm_GenLoc_end = 35226253
    | Mm_Uniprot = P42859
  }}
}}
<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{PBB_Summary
| section_title =
| summary_text =
}}
'''Huntingtin''' (Htt) is the protein coded by the [[HD (gene)|HD gene]] (which itself is sometimes called the Huntingtin gene). It is variable in its structure. There are many polymorphisms of the HD gene which can lead to variable numbers of glutamine residues present. In its [[wild-type]] (normal) form, it contains 6-34 glutamine residues. In individuals affected by Huntington's Disease, an [[autosomal dominant]] [[genetic disorder]], it contains between 35-155 glutamine residues. Huntingtin has a predicted mass of ~350kDa, however, this varies and is largely dependent on the number of glutamine residues in the protein. Normal huntingtin is generally accepted to be 3144 amino acids in size.


==Function==
It is variable in its structure, as the many [[Polymorphism (biology)|polymorphisms]] of the gene can lead to variable numbers of [[glutamine]] residues present in the protein. In its [[wild-type]] (normal) form, it contains 6-35 [[glutamine]] residues. However, in individuals affected by [[Huntington's disease]] (an [[autosomal dominant]] [[genetic disorder]]), it contains more than 36 glutamine residues (highest reported repeat length is about 250).<ref name="pmid9932964">{{cite journal | vauthors = Nance MA, Mathias-Hagen V, Breningstall G, Wick MJ, McGlennen RC | title = Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington's disease | journal = Neurology | volume = 52 | issue = 2 | pages = 392–4 | date = Jan 1999 | pmid = 9932964 | doi = 10.1212/wnl.52.2.392 | url = http://www.neurology.org/cgi/content/abstract/52/2/392 }}</ref> Its commonly used name is derived from this disease; previously, the ''IT15'' label was commonly used.
The function of Huntingtin is unclear. It is essential for development and absence of huntingtin is lethal in mice.<ref name=Nasir>{{ cite journal | author=Nasir J, Floresco S, et al | title=Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes | journal =Cell  | volume = 81 | pages=811–823 | date=1995 | doi=10.1016/0092-8674(95)90542-1}}</ref> The protein has no sequence [[homology]] with other proteins and is highly expressed in neurons and testes in humans and rodents.<ref name=Cattaneo>{{cite journal | author=Cattaneo E, Zuccato C, Tartari M | title=Normal huntingtin function: an alternative approach to Huntington's disease | journal = Nature Reviews Neuroscience | volume = 6 | pages= 919-930 | date=2005 Dec | doi=10.1038/nrn1806}}</ref> It has however been experimentally demonstrated that Huntingtin acts as a [[transcription  factor]] in upregulating the expression of [[BDNF|Brain Derived Neurotrophic Factor (BDNF)]]. In the deficient protein, there is suppression of this [[Transcription (genetics)|transcription]] regulatory function of Huntingtin and hence underexpression of BDNF.<ref name=Zuccato>{{cite journal | author=Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, et al | title=Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease | journal=Science | date=2001 Jul 20 | volume = 293| issue=5529 | pages=445-6}}</ref>


From [[immunohistochemistry]], [[electron microscopy]], [[subcellular fractionation]] studies of the molecule, it has been found that Huntingtin is primarily associated with [[vesicles]] and [[microtubules]].<ref name=Hoffner>{{cite journal | author=Hoffner G, Kahlem P, Djian P | title=Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with β-tubulin: relevance to Huntington's disease | journal= J Cell Sci | volume=115 | pages=941–948 | date=2002}}</ref><ref name=DiFiglia>{{cite journal | author=DiFiglia M, et al. | title = Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons | journal=Neuron | volume=14 | pages = 1075–1081 | date=1995}}</ref>.These appear to indicate a functional role in cytoskeletal anchoring or transport of [[mitochondria]].
The mass of huntingtin protein is dependent largely on the number of glutamine residues it has, the predicted mass is around 350&nbsp;[[Atomic mass unit|kDa]]. Normal huntingtin is generally accepted to be 3144 amino acids in size. The exact function of this protein is not known, but it plays an important role in [[nerve cell]]s. Within cells, huntingtin may be involved in signaling, transporting materials, binding proteins and other structures, and protecting against programmed cell death ([[apoptosis]]). The huntingtin protein is required for normal development before [[birth]].<ref name="pmid7774020">{{cite journal | vauthors = Nasir J, Floresco SB, O'Kusky JR, Diewert VM, Richman JM, Zeisler J, Borowski A, Marth JD, Phillips AG, Hayden MR | title = Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes | journal = Cell | volume = 81 | issue = 5 | pages = 811–23 | date = Jun 1995 | pmid = 7774020 | doi = 10.1016/0092-8674(95)90542-1 }}</ref> It is expressed in many tissues in the body, with the highest levels of expression seen in the brain.


Huntingtin has also been found to interact with a number of [[proteins]]. One such protein is the Huntingtin Interacting Protein I ([[Hip-1|HIP-I/Hip-1]]).<ref name=Wanker>{{cite journal | author=Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Walter S, et al | title=HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system | journal = Hum. Mol. Genet. | date=1997 Mar | volume = 6 | issue = 3 | pages = 487-95}} </ref> Unfortunately the actions mediated via these interactions of huntingtin with the complementary interacting proteins are not fully understood.
== Gene ==


== Abnormal huntingtin (mHtt) ==
The 5' end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid [[glutamine]], that is repeated multiple times. This region is called a [[trinucleotide repeat]]. Normal persons have a CAG repeat count of between seven and 35 repeats.
The key sequence which is found in [[Huntington's disease]] (HD) is a stretch of [[glutamine]] residues beginning at the 18th amino acid. In unaffected individuals, this stretch contains between 9 and 35 glutamine residues with no adverse effects.<ref name=Collaboration>{{cite journal | author=Huntington's Disease Collaborative Research Group | title=A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes | journal = Cell | volume =72 | pages=971–983 | date=1993}}</ref> However, individuals with HD have an expansion up to around 100 glutamines in this region of the gene. A greater number of residues is associated with earlier onset of the disease.


==History==
The HD gene is located on the short (p) arm of [[chromosome 4 (human)|chromosome 4]] at position 16.3, from [[base pair]] 3,074,510 to base pair 3,243,960.<ref>http://ghr.nlm.nih.gov/gene/HTT</ref>
Huntingtin was identified in 1993.<ref>{{cite journal |author= |title=A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group |journal=Cell |volume=72 |issue=6 |pages=971-83 |year=1993 |pmid=8458085}}</ref>


==References==
== Protein ==
{{reflist|2}}
 
==Further reading==
=== Function ===
{{refbegin | 2}}
The function of huntingtin is unclear. It is essential for development, and absence of huntingtin is lethal in mice.<ref name="pmid7774020"/> The protein has no [[sequence homology]] with other proteins and is highly expressed in neurons and testes in humans and rodents.<ref name="pmid16288298">{{cite journal | vauthors = Cattaneo E, Zuccato C, Tartari M | title = Normal huntingtin function: an alternative approach to Huntington's disease | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 12 | pages = 919–30 | date = Dec 2005 | pmid = 16288298 | doi = 10.1038/nrn1806 }}</ref> Huntingtin upregulates the expression of Brain Derived Neurotrophic Factor ([[brain-derived neurotrophic factor|BDNF]]) at the transcription level, but the mechanism by which huntingtin regulates gene expression has not been determined.<ref name="pmid11408619">{{cite journal | vauthors = Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E | title = Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease | journal = Science | volume = 293 | issue = 5529 | pages = 493–8 | date = Jul 2001 | pmid = 11408619 | doi = 10.1126/science.1059581 }}</ref> From [[immunohistochemistry]], [[electron microscopy]], and [[subcellular fractionation]] studies of the molecule, it has been found that huntingtin is primarily associated with [[vesicle (biology)|vesicle]]s and [[microtubules]].<ref name="pmid11870213">{{cite journal | vauthors = Hoffner G, Kahlem P, Djian P | title = Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with beta-tubulin: relevance to Huntington's disease | journal = Journal of Cell Science | volume = 115 | issue = Pt 5 | pages = 941–8 | date = Mar 2002 | pmid = 11870213 | doi =  | url = http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=11870213 }}</ref><ref name="pmid7748555">{{cite journal | vauthors = DiFiglia M, Sapp E, Chase K, Schwarz C, Meloni A, Young C, Martin E, Vonsattel JP, Carraway R, Reeves SA | title = Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons | journal = Neuron | volume = 14 | issue = 5 | pages = 1075–81 | date = May 1995 | pmid = 7748555 | doi = 10.1016/0896-6273(95)90346-1 }}</ref> These appear to indicate a functional role in cytoskeletal anchoring or transport of [[mitochondria]]. The Htt protein is involved in [[vesicle (biology)|vesicle]] trafficking as it interacts with HIP1, a [[clathrin]]-binding protein, to mediate [[endocytosis]], the trafficking of materials into a cell.<ref name="pmid9682010">{{cite journal | vauthors = Velier J, Kim M, Schwarz C, Kim TW, Sapp E, Chase K, Aronin N, DiFiglia M | title = Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways | journal = Experimental Neurology | volume = 152 | issue = 1 | pages = 34–40 | date = Jul 1998 | pmid = 9682010 | doi = 10.1006/exnr.1998.6832 }}</ref><ref name="pmid11532990">{{cite journal | vauthors = Waelter S, Scherzinger E, Hasenbank R, Nordhoff E, Lurz R, Goehler H, Gauss C, Sathasivam K, Bates GP, Lehrach H, Wanker EE | title = The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis | journal = Human Molecular Genetics | volume = 10 | issue = 17 | pages = 1807–17 | date = Aug 2001 | pmid = 11532990 | doi = 10.1093/hmg/10.17.1807 }}</ref> Huntingtin has also been shown to have a role in the establishment in [[epithelial polarity]] through its interaction with [[RAB11A]].<ref>{{cite journal | vauthors = Elias S, McGuire JR, Yu H, Humbert S | title = Huntingtin Is Required for Epithelial Polarity through RAB11A-Mediated Apical Trafficking of PAR3-aPKC | journal = PLoS Biology | volume = 13 | issue = 5 | pages = e1002142 | date = May 2015 | pmid = 25942483 | doi = 10.1371/journal.pbio.1002142 | url = http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002142 | pmc=4420272}}
{{PBB_Further_reading
</ref>
| citations =  
 
*{{cite journal | author=MacDonald ME, Novelletto A, Lin C, ''et al.'' |title=The Huntington's disease candidate region exhibits many different haplotypes. |journal=Nat. Genet. |volume=1 |issue= 2 |pages= 99-103 |year= 1993 |pmid= 1302016 |doi= 10.1038/ng0592-99 }}
=== Interactions ===
*{{cite journal | author=Jones AL |title=The localization and interactions of huntingtin. |journal=Philos. Trans. R. Soc. Lond., B, Biol. Sci. |volume=354 |issue= 1386 |pages= 1021-7 |year= 1999 |pmid= 10434301 |doi= 10.1098/rstb.1999.0454 }}
 
*{{cite journal | author=Young AB |title=Huntingtin in health and disease. |journal=J. Clin. Invest. |volume=111 |issue= 3 |pages= 299-302 |year= 2003 |pmid= 12569151 |doi= }}
Huntingtin has been found to interact directly with at least 19 other [[proteins]], of which six are used for transcription, four for transport, three for cell signalling, and six others of unknown function (HIP5, HIP11, HIP13, HIP15, HIP16, and CGI-125).<ref name="pmid12932731">{{cite journal | vauthors = Harjes P, Wanker EE | title = The hunt for huntingtin function: interaction partners tell many different stories | journal = Trends in Biochemical Sciences | volume = 28 | issue = 8 | pages = 425–33 | date = Aug 2003 | pmid = 12932731 | doi = 10.1016/S0968-0004(03)00168-3 }}</ref>  Over 100 interacting proteins have been found, such as [[huntingtin-associated protein 1]] (HAP1) and [[Hip-1|huntingtin interacting protein 1]] (HIP1), these were typically found using [[two-hybrid screening]] and confirmed using [[immunoprecipitation]].<ref name="pmid15383276">{{cite journal | vauthors = Goehler H, Lalowski M, Stelzl U, Waelter S, Stroedicke M, Worm U, Droege A, Lindenberg KS, Knoblich M, Haenig C, Herbst M, Suopanki J, Scherzinger E, Abraham C, Bauer B, Hasenbank R, Fritzsche A, Ludewig AH, Büssow K, Buessow K, Coleman SH, Gutekunst CA, Landwehrmeyer BG, Lehrach H, Wanker EE | title = A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease | journal = Molecular Cell | volume = 15 | issue = 6 | pages = 853–65 | date = Sep 2004 | pmid = 15383276 | doi = 10.1016/j.molcel.2004.09.016 | url = http://linkinghub.elsevier.com/retrieve/pii/S1097276504005453 }}</ref><ref name=Wanker>{{cite journal | vauthors = Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Wälter S, Tait D, Colicelli J, Lehrach H | title = HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system | journal = Human Molecular Genetics | volume = 6 | issue = 3 | pages = 487–95 | date = Mar 1997 | pmid = 9147654 | doi = 10.1093/hmg/6.3.487 }}</ref>
*{{cite journal | author=Rangone H, Humbert S, Saudou F |title=Huntington's disease: how does huntingtin, an anti-apoptotic protein, become toxic? |journal=Pathol. Biol. |volume=52 |issue= 6 |pages= 338-42 |year= 2004 |pmid= 15261377 |doi= 10.1016/j.patbio.2003.06.004 }}
 
*{{cite journal | author=Li SH, Li XJ |title=Huntingtin and its role in neuronal degeneration. |journal=The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry |volume=10 |issue= 5 |pages= 467-75 |year= 2005 |pmid= 15359012 |doi= 10.1177/1073858404266777 }}
{| class="wikitable"
*{{cite journal | author=Myers RH |title=Huntington's disease genetics. |journal=NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics |volume=1 |issue= 2 |pages= 255-62 |year= 2005 |pmid= 15717026 |doi= }}
|-
}}
! Interacting Protein
! PolyQ length dependence
! Function
|-
| α-adaptin C/[[AP2A2|HYPJ]]
| Yes
| Endocytosis
|-
| [[AKT1|Akt]]/PKB
| No
| Kinase
|-
| [[CREB binding protein|CBP]]
| Yes
| Transcriptional co-activator with acetyltransferase activity
|-
| [[Transcription elongation regulator 1|CA150]]
| No
| Transcriptional activator
|-
| [[TRIP10|CIP4]]
| Yes
| cdc42-dependent signal transduction
|-
| [[RBBP8|CtBP]]
| Yes
| Transcription factor
|-
| [[Optineurin|FIP2]]
| Not known
| Cell morphogenesis
|-
| [[Grb2]]<ref name=pmid9079622>{{cite journal | vauthors = Liu YF, Deth RC, Devys D | title = SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes | journal = The Journal of Biological Chemistry | volume = 272 | issue = 13 | pages = 8121–4 | date = Mar 1997 | pmid = 9079622 | doi = 10.1074/jbc.272.13.8121 }}</ref>
| Not known
| Growth factor receptor binding protein
|-
| [[Huntingtin-associated protein 1|HAP1]]
| Yes
| Membrane trafficking
|-
| HAP40
| Not known
| Unknown
|-
| [[Hip-1|HIP1]]
| Yes
| Endocytosis, proapoptotic
|-
| [[ZDHHC17|HIP14]]/HYP-H
| Yes
| Trafficking, endocytosis
|-
| [[Nuclear receptor co-repressor 1|N-CoR]]
| Yes
| Nuclear receptor co-repressor
|-
| [[NF-κB]]
| Not known
| Transcription factor
|-
| [[p53]]<ref name=pmid10823891>{{cite journal | vauthors = Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, Wanker EE, Bates GP, Housman DE, Thompson LM | title = The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 12 | pages = 6763–8 | date = Jun 2000 | pmid = 10823891 | pmc = 18731 | doi = 10.1073/pnas.100110097 }}</ref>
| No
| Transcription factor
|-
| [[PACSIN1]]<ref name=pmid12354780>{{cite journal | vauthors = Modregger J, DiProspero NA, Charles V, Tagle DA, Plomann M | title = PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington's disease brains | journal = Human Molecular Genetics | volume = 11 | issue = 21 | pages = 2547–58 | date = Oct 2002 | pmid = 12354780 | doi = 10.1093/hmg/11.21.2547 }}</ref>
| Yes
| Endocytosis, actin cytoskeleton
|-
| PSD-95
| Yes
| Postsynaptic Density 95
|-
| RasGAP
| Not known
| Ras GTPase activating protein
|-
| [[SH3GL3]]<ref name=pmid9809064>{{cite journal | vauthors = Sittler A, Wälter S, Wedemeyer N, Hasenbank R, Scherzinger E, Eickhoff H, Bates GP, Lehrach H, Wanker EE | title = SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates | journal = Molecular Cell | volume = 2 | issue = 4 | pages = 427–36 | date = Oct 1998 | pmid = 9809064 | doi = 10.1016/S1097-2765(00)80142-2 }}</ref>
| Yes
| Endocytosis
|-
| [[SIN3A]]
| Yes
| Transcriptional repressor
|-
| [[Sp1 transcription factor|Sp1]]<ref name=pmid11839795>{{cite journal | vauthors = Li SH, Cheng AL, Zhou H, Lam S, Rao M, Li H, Li XJ | title = Interaction of Huntington disease protein with transcriptional activator Sp1 | journal = Molecular and Cellular Biology | volume = 22 | issue = 5 | pages = 1277–87 | date = Mar 2002 | pmid = 11839795 | pmc = 134707 | doi = 10.1128/MCB.22.5.1277-1287.2002 }}</ref>
| Yes
| Transcription factor
|}
 
Huntingtin has also been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[HIP2]],<ref name="pmid8702625">{{cite journal | vauthors = Kalchman MA, Graham RK, Xia G, Koide HB, Hodgson JG, Graham KC, Goldberg YP, Gietz RD, Pickart CM, Hayden MR | title = Huntingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme | journal = The Journal of Biological Chemistry | volume = 271 | issue = 32 | pages = 19385–94 | date = Aug 1996 | pmid = 8702625 | doi = 10.1074/jbc.271.32.19385 }}</ref>
* [[MAP3K10]],<ref name="pmid10801775">{{cite journal | vauthors = Liu YF, Dorow D, Marshall J | title = Activation of MLK2-mediated signaling cascades by polyglutamine-expanded huntingtin | journal = The Journal of Biological Chemistry | volume = 275 | issue = 25 | pages = 19035–40 | date = Jun 2000 | pmid = 10801775 | doi = 10.1074/jbc.C000180200 }}</ref>
* [[Optineurin|OPTN]],<ref name="pmid11137014">{{cite journal | vauthors = Hattula K, Peränen J | title = FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates cellular morphogenesis | journal = Current Biology | volume = 10 | issue = 24 | pages = 1603–6 | year = 2000 | pmid = 11137014 | doi = 10.1016/S0960-9822(00)00864-2 }}</ref>
* [[PRPF40A]],<ref name=pmid9700202/>
* [[RAS p21 protein activator 1|RASA1]],<ref name=pmid9079622/>
* [[SETD2]],<ref name="pmid9700202">{{cite journal | vauthors = Faber PW, Barnes GT, Srinidhi J, Chen J, Gusella JF, MacDonald ME | title = Huntingtin interacts with a family of WW domain proteins | journal = Human Molecular Genetics | volume = 7 | issue = 9 | pages = 1463–74 | date = Sep 1998 | pmid = 9700202 | doi = 10.1093/hmg/7.9.1463 }}</ref>
* [[TRIP10]],<ref name="pmid12604778">{{cite journal | vauthors = Holbert S, Dedeoglu A, Humbert S, Saudou F, Ferrante RJ, Néri C | title = Cdc42-interacting protein 4 binds to huntingtin: neuropathologic and biological evidence for a role in Huntington's disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 5 | pages = 2712–7 | date = Mar 2003 | pmid = 12604778 | pmc = 151406 | doi = 10.1073/pnas.0437967100 }}</ref>
* [[ZDHHC17]].<ref name=pmid9700202/><ref name="pmid12393793">{{cite journal | vauthors = Singaraja RR, Hadano S, Metzler M, Givan S, Wellington CL, Warby S, Yanai A, Gutekunst CA, Leavitt BR, Yi H, Fichter K, Gan L, McCutcheon K, Chopra V, Michel J, Hersch SM, Ikeda JE, Hayden MR | title = HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis | journal = Human Molecular Genetics | volume = 11 | issue = 23 | pages = 2815–28 | date = Nov 2002 | pmid = 12393793 | doi = 10.1093/hmg/11.23.2815 }}</ref>
{{Div col end}}
 
== Clinical significance ==
{{main article|Huntington's disease}}
{| class="wikitable" border="1" style="float:right; margin-left:15px; text-align:center;"
|+Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats<ref name="lancet220"/>
|-
! Repeat count
! Classification
! Disease status
|-
| <26
| Normal
| Unaffected
|-
| 27–35
| Intermediate
| Unaffected
|-
| 36–40
| Reduced penetrance
| +/- Affected
|-
| >40
| Full penetrance
| Affected
|}
 
[[Huntington's disease]] (HD) is caused by a mutated form of the huntingtin gene, where excessive (more than 36) CAG repeats result in formation of an unstable protein.<ref name="lancet220">{{cite journal | vauthors = Walker FO | title = Huntington's disease | journal = Lancet | volume = 369 | issue = 9557 | pages = 218–28 | date = Jan 2007 | pmid = 17240289 | doi = 10.1016/S0140-6736(07)60111-1 }}</ref> These expanded repeats lead to production of a huntingtin protein that contains an abnormally long [[polyglutamine tract]] at the N-terminus. This makes it part of a class of neurodegenerative disorders known as [[trinucleotide repeat disorders]] or polyglutamine disorders. The key sequence which is found in Huntington's disease is a [[Trinucleotide repeat disorders|trinucleotide repeat expansion]] of [[glutamine]] residues beginning at the 18th amino acid. In unaffected individuals, this contains between 9 and 35 glutamine residues with no adverse effects.<ref name="pmid8458085" /> However, 36 or more residues produce an erroneous form of Htt, '''mHtt''' (standing for mutant Htt). Reduced penetrance is found in counts 36-39.<ref name="pmid9063751">{{cite journal | vauthors = Chong SS, Almqvist E, Telenius H, LaTray L, Nichol K, Bourdelat-Parks B, Goldberg YP, Haddad BR, Richards F, Sillence D, Greenberg CR, Ives E, Van den Engh G, Hughes MR, Hayden MR | title = Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses | journal = Human Molecular Genetics | volume = 6 | issue = 2 | pages = 301–9 | date = Feb 1997 | pmid = 9063751 | doi = 10.1093/hmg/6.2.301 }}</ref>
 
Enzymes in the cell often cut this elongated protein into fragments. The protein fragments form abnormal clumps, known as neuronal intranuclear inclusions (NIIs), inside nerve cells, and may attract other, normal proteins into the clumps. The presence of these clumps was once thought to play a causal role in Huntington disease.<ref name="pmid9267033">{{cite journal | vauthors = Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP | title = Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation | journal = Cell | volume = 90 | issue = 3 | pages = 537–48 | date = Aug 1997 | pmid = 9267033 | doi = 10.1016/S0092-8674(00)80513-9 }}</ref>  Further research undermined this conclusion by showing the presence of NIIs actually extended the life of neurons and acted to reduce intracellular mutant huntingtin in neighboring neurons.<ref>{{cite journal | vauthors = Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S | title = Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death | journal = Nature | volume = 431 | issue = 7010 | pages = 805–10 | date = Oct 2004 | pmid = 15483602 | doi = 10.1038/nature02998 }}</ref> Thus, the likelihood of neuronal death can be predicted by accounting for two factors: (1) the length of CAG repeats in the Huntingtin gene and (2) the neuron's exposure to diffuse intracellular mutant huntingtin protein.  NIIs (protein clumping) can thereby be construed as a coping mechanism—as opposed to a pathogenic mechanism—to stem neuronal death by decreasing the amount of diffuse huntingtin.<ref name="pmid15483586">{{cite journal | vauthors = Orr HT | title = Neurodegenerative disease: neuron protection agency | journal = Nature | volume = 431 | issue = 7010 | pages = 747–8 | date = Oct 2004 | pmid = 15483586 | doi = 10.1038/431747a }}</ref> This process is particularly likely to occur in the [[striatum]] (a part of the brain that coordinates movement) primarily, and the [[frontal cortex]] (a part of the brain that controls thinking and emotions).
 
People with 36 to 40 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with more than 40 repeats will develop the disorder during a normal lifetime. When there are more than 60 CAG repeats, the person develops a severe form of HD known as [[Juvenile Huntington's disease|juvenile HD]]. Therefore, the number of CAG (the sequence coding for the amino acid glutamine) repeats influences the age of onset of the disease. No case of HD has been diagnosed with a count less than 36.<ref name="pmid9063751" />
 
As the altered gene is passed from one generation to the next, the size of the CAG repeat expansion can change; it often increases in size, especially when it is inherited from the father. People with 28 to 35 CAG repeats have not been reported to develop the disorder, but their children are at risk of having the disease if the repeat expansion increases.
{{Clear}}
 
== References ==
{{Reflist|35em}}
 
== Further reading ==
{{refbegin|35em}}
* {{cite journal | vauthors = Bates G | title = Huntingtin aggregation and toxicity in Huntington's disease | journal = Lancet | volume = 361 | issue = 9369 | pages = 1642–4 | date = May 2003 | pmid = 12747895 | doi = 10.1016/S0140-6736(03)13304-1 }}
* {{cite journal | vauthors = Cattaneo E | title = Dysfunction of wild-type huntingtin in Huntington disease | journal = News in Physiological Sciences | volume = 18 | pages = 34–7 | date = Feb 2003 | pmid = 12531930 | doi = 10.1152/nips.01410.2002 }}
* {{cite journal | vauthors = Gárdián G, Vécsei L | title = Huntington's disease: pathomechanism and therapeutic perspectives | journal = Journal of Neural Transmission | volume = 111 | issue = 10-11 | pages = 1485–94 | date = Oct 2004 | pmid = 15480847 | doi = 10.1007/s00702-004-0201-4 }}
* {{cite journal | vauthors = Landles C, Bates GP | title = Huntingtin and the molecular pathogenesis of Huntington's disease. Fourth in molecular medicine review series | journal = EMBO Reports | volume = 5 | issue = 10 | pages = 958–63 | date = Oct 2004 | pmid = 15459747 | pmc = 1299150 | doi = 10.1038/sj.embor.7400250 }}
* {{cite journal | vauthors = Jones AL | title = The localization and interactions of huntingtin | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 354 | issue = 1386 | pages = 1021–7 | date = Jun 1999 | pmid = 10434301 | pmc = 1692601 | doi = 10.1098/rstb.1999.0454 }}
* {{cite journal | vauthors = Li SH, Li XJ | title = Huntingtin and its role in neuronal degeneration | journal = The Neuroscientist | volume = 10 | issue = 5 | pages = 467–75 | date = Oct 2004 | pmid = 15359012 | doi = 10.1177/1073858404266777 }}
* {{cite journal | vauthors = MacDonald ME, Novelletto A, Lin C, Tagle D, Barnes G, Bates G, Taylor S, Allitto B, Altherr M, Myers R | title = The Huntington's disease candidate region exhibits many different haplotypes | journal = Nature Genetics | volume = 1 | issue = 2 | pages = 99–103 | date = May 1992 | pmid = 1302016 | doi = 10.1038/ng0592-99 }}
* {{cite journal | vauthors = MacDonald ME | title = Huntingtin: alive and well and working in middle management | journal = Science's STKE | volume = 2003 | issue = 207 | pages = pe48 | date = Nov 2003 | pmid = 14600292 | doi = 10.1126/stke.2003.207.pe48 }}
* {{cite journal | vauthors = Myers RH | title = Huntington's disease genetics | journal = NeuroRx | volume = 1 | issue = 2 | pages = 255–62 | date = Apr 2004 | pmid = 15717026 | pmc = 534940 | doi = 10.1602/neurorx.1.2.255 }}
* {{cite journal | vauthors = Rangone H, Humbert S, Saudou F | title = Huntington's disease: how does huntingtin, an anti-apoptotic protein, become toxic? | journal = Pathologie-Biologie | volume = 52 | issue = 6 | pages = 338–42 | date = Jul 2004 | pmid = 15261377 | doi = 10.1016/j.patbio.2003.06.004 }}
* {{cite journal | vauthors = Young AB | title = Huntingtin in health and disease | journal = The Journal of Clinical Investigation | volume = 111 | issue = 3 | pages = 299–302 | date = Feb 2003 | pmid = 12569151 | pmc = 151871 | doi = 10.1172/JCI17742 }}
{{refend}}
{{refend}}
== See also ==
 
*[[Huntingtin-associated protein 1|HAP1]] Huntingtin-associated protein
*[[hip-1]] Huntingtin Interacting Protein
== External links ==
== External links ==
* {{MeshName|Huntingtin+protein,+human}}
* {{MeshName|Huntingtin+protein,+human}}
* [https://web.archive.org/web/20090327130709/http://www.stanford.edu/group/hopes/causes/huntprot/p1.html The Huntingtin Protein and Protein Aggregation] at [http://hopes.stanford.edu/ HOPES] : Huntington's Outreach Project for Education at Stanford
* [http://www.hda.org.uk/ The HDA]  Huntington's Disease Association UK
* {{OMIM|143100}}
* {{EntrezGene|3064}}
* [https://web.archive.org/web/19980211231514/http://bioinformatics.weizmann.ac.il/cards-bin/carddisp?HD GeneCard]
* [http://www.ihop-net.org/UniPub/iHOP/bng/88980.html iHOP]


[[Category:Proteins]]
[[Category:Human genes]]
 
[[Category:Human proteins]]
[[fr:Huntingtine]]
[[Category:Huntington's disease]]
[[no:Huntingtin]]
[[Category:Genes on human chromosome 4]]
{{WikiDoc Sources}}

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The huntingtin gene, also called the HTT or HD (Huntington disease) gene, is the IT15 ("interesting transcript 15") gene, which codes for a protein called the huntingtin protein.[1] The gene and its product are under heavy investigation as part of Huntington's disease clinical research and the suggested role for huntingtin in long-term memory storage.[2]

It is variable in its structure, as the many polymorphisms of the gene can lead to variable numbers of glutamine residues present in the protein. In its wild-type (normal) form, it contains 6-35 glutamine residues. However, in individuals affected by Huntington's disease (an autosomal dominant genetic disorder), it contains more than 36 glutamine residues (highest reported repeat length is about 250).[3] Its commonly used name is derived from this disease; previously, the IT15 label was commonly used.

The mass of huntingtin protein is dependent largely on the number of glutamine residues it has, the predicted mass is around 350 kDa. Normal huntingtin is generally accepted to be 3144 amino acids in size. The exact function of this protein is not known, but it plays an important role in nerve cells. Within cells, huntingtin may be involved in signaling, transporting materials, binding proteins and other structures, and protecting against programmed cell death (apoptosis). The huntingtin protein is required for normal development before birth.[4] It is expressed in many tissues in the body, with the highest levels of expression seen in the brain.

Gene

The 5' end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid glutamine, that is repeated multiple times. This region is called a trinucleotide repeat. Normal persons have a CAG repeat count of between seven and 35 repeats.

The HD gene is located on the short (p) arm of chromosome 4 at position 16.3, from base pair 3,074,510 to base pair 3,243,960.[5]

Protein

Function

The function of huntingtin is unclear. It is essential for development, and absence of huntingtin is lethal in mice.[4] The protein has no sequence homology with other proteins and is highly expressed in neurons and testes in humans and rodents.[6] Huntingtin upregulates the expression of Brain Derived Neurotrophic Factor (BDNF) at the transcription level, but the mechanism by which huntingtin regulates gene expression has not been determined.[7] From immunohistochemistry, electron microscopy, and subcellular fractionation studies of the molecule, it has been found that huntingtin is primarily associated with vesicles and microtubules.[8][9] These appear to indicate a functional role in cytoskeletal anchoring or transport of mitochondria. The Htt protein is involved in vesicle trafficking as it interacts with HIP1, a clathrin-binding protein, to mediate endocytosis, the trafficking of materials into a cell.[10][11] Huntingtin has also been shown to have a role in the establishment in epithelial polarity through its interaction with RAB11A.[12]

Interactions

Huntingtin has been found to interact directly with at least 19 other proteins, of which six are used for transcription, four for transport, three for cell signalling, and six others of unknown function (HIP5, HIP11, HIP13, HIP15, HIP16, and CGI-125).[13] Over 100 interacting proteins have been found, such as huntingtin-associated protein 1 (HAP1) and huntingtin interacting protein 1 (HIP1), these were typically found using two-hybrid screening and confirmed using immunoprecipitation.[14][15]

Interacting Protein PolyQ length dependence Function
α-adaptin C/HYPJ Yes Endocytosis
Akt/PKB No Kinase
CBP Yes Transcriptional co-activator with acetyltransferase activity
CA150 No Transcriptional activator
CIP4 Yes cdc42-dependent signal transduction
CtBP Yes Transcription factor
FIP2 Not known Cell morphogenesis
Grb2[16] Not known Growth factor receptor binding protein
HAP1 Yes Membrane trafficking
HAP40 Not known Unknown
HIP1 Yes Endocytosis, proapoptotic
HIP14/HYP-H Yes Trafficking, endocytosis
N-CoR Yes Nuclear receptor co-repressor
NF-κB Not known Transcription factor
p53[17] No Transcription factor
PACSIN1[18] Yes Endocytosis, actin cytoskeleton
PSD-95 Yes Postsynaptic Density 95
RasGAP Not known Ras GTPase activating protein
SH3GL3[19] Yes Endocytosis
SIN3A Yes Transcriptional repressor
Sp1[20] Yes Transcription factor

Huntingtin has also been shown to interact with:

Clinical significance

Main article: Huntington's disease
Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats[27]
Repeat count Classification Disease status
<26 Normal Unaffected
27–35 Intermediate Unaffected
36–40 Reduced penetrance +/- Affected
>40 Full penetrance Affected

Huntington's disease (HD) is caused by a mutated form of the huntingtin gene, where excessive (more than 36) CAG repeats result in formation of an unstable protein.[27] These expanded repeats lead to production of a huntingtin protein that contains an abnormally long polyglutamine tract at the N-terminus. This makes it part of a class of neurodegenerative disorders known as trinucleotide repeat disorders or polyglutamine disorders. The key sequence which is found in Huntington's disease is a trinucleotide repeat expansion of glutamine residues beginning at the 18th amino acid. In unaffected individuals, this contains between 9 and 35 glutamine residues with no adverse effects.[1] However, 36 or more residues produce an erroneous form of Htt, mHtt (standing for mutant Htt). Reduced penetrance is found in counts 36-39.[28]

Enzymes in the cell often cut this elongated protein into fragments. The protein fragments form abnormal clumps, known as neuronal intranuclear inclusions (NIIs), inside nerve cells, and may attract other, normal proteins into the clumps. The presence of these clumps was once thought to play a causal role in Huntington disease.[29] Further research undermined this conclusion by showing the presence of NIIs actually extended the life of neurons and acted to reduce intracellular mutant huntingtin in neighboring neurons.[30] Thus, the likelihood of neuronal death can be predicted by accounting for two factors: (1) the length of CAG repeats in the Huntingtin gene and (2) the neuron's exposure to diffuse intracellular mutant huntingtin protein. NIIs (protein clumping) can thereby be construed as a coping mechanism—as opposed to a pathogenic mechanism—to stem neuronal death by decreasing the amount of diffuse huntingtin.[31] This process is particularly likely to occur in the striatum (a part of the brain that coordinates movement) primarily, and the frontal cortex (a part of the brain that controls thinking and emotions).

People with 36 to 40 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with more than 40 repeats will develop the disorder during a normal lifetime. When there are more than 60 CAG repeats, the person develops a severe form of HD known as juvenile HD. Therefore, the number of CAG (the sequence coding for the amino acid glutamine) repeats influences the age of onset of the disease. No case of HD has been diagnosed with a count less than 36.[28]

As the altered gene is passed from one generation to the next, the size of the CAG repeat expansion can change; it often increases in size, especially when it is inherited from the father. People with 28 to 35 CAG repeats have not been reported to develop the disorder, but their children are at risk of having the disease if the repeat expansion increases.

References

  1. ↑ 1.0 1.1 The Huntington's Disease Collaborative Research Group (Mar 1993). "A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group". Cell. 72 (6): 971–83. doi:10.1016/0092-8674(93)90585-E. PMID 8458085.
  2. ↑ Choi YB, Kadakkuzha BM, Liu XA, Akhmedov K, Kandel ER, Puthanveettil SV (July 23, 2014). "Huntingtin is critical both pre- and postsynaptically for long-term learning-related synaptic plasticity in Aplysia". PLOS ONE. 9 (7): e103004. doi:10.1371/journal.pone.0103004. PMC 4108396. PMID 25054562.
  3. ↑ Nance MA, Mathias-Hagen V, Breningstall G, Wick MJ, McGlennen RC (Jan 1999). "Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington's disease". Neurology. 52 (2): 392–4. doi:10.1212/wnl.52.2.392. PMID 9932964.
  4. ↑ 4.0 4.1 Nasir J, Floresco SB, O'Kusky JR, Diewert VM, Richman JM, Zeisler J, Borowski A, Marth JD, Phillips AG, Hayden MR (Jun 1995). "Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes". Cell. 81 (5): 811–23. doi:10.1016/0092-8674(95)90542-1. PMID 7774020.
  5. ↑ http://ghr.nlm.nih.gov/gene/HTT
  6. ↑ Cattaneo E, Zuccato C, Tartari M (Dec 2005). "Normal huntingtin function: an alternative approach to Huntington's disease". Nature Reviews. Neuroscience. 6 (12): 919–30. doi:10.1038/nrn1806. PMID 16288298.
  7. ↑ Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E (Jul 2001). "Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease". Science. 293 (5529): 493–8. doi:10.1126/science.1059581. PMID 11408619.
  8. ↑ Hoffner G, Kahlem P, Djian P (Mar 2002). "Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with beta-tubulin: relevance to Huntington's disease". Journal of Cell Science. 115 (Pt 5): 941–8. PMID 11870213.
  9. ↑ DiFiglia M, Sapp E, Chase K, Schwarz C, Meloni A, Young C, Martin E, Vonsattel JP, Carraway R, Reeves SA (May 1995). "Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons". Neuron. 14 (5): 1075–81. doi:10.1016/0896-6273(95)90346-1. PMID 7748555.
  10. ↑ Velier J, Kim M, Schwarz C, Kim TW, Sapp E, Chase K, Aronin N, DiFiglia M (Jul 1998). "Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways". Experimental Neurology. 152 (1): 34–40. doi:10.1006/exnr.1998.6832. PMID 9682010.
  11. ↑ Waelter S, Scherzinger E, Hasenbank R, Nordhoff E, Lurz R, Goehler H, Gauss C, Sathasivam K, Bates GP, Lehrach H, Wanker EE (Aug 2001). "The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis". Human Molecular Genetics. 10 (17): 1807–17. doi:10.1093/hmg/10.17.1807. PMID 11532990.
  12. ↑ Elias S, McGuire JR, Yu H, Humbert S (May 2015). "Huntingtin Is Required for Epithelial Polarity through RAB11A-Mediated Apical Trafficking of PAR3-aPKC". PLoS Biology. 13 (5): e1002142. doi:10.1371/journal.pbio.1002142. PMC 4420272. PMID 25942483.
  13. ↑ Harjes P, Wanker EE (Aug 2003). "The hunt for huntingtin function: interaction partners tell many different stories". Trends in Biochemical Sciences. 28 (8): 425–33. doi:10.1016/S0968-0004(03)00168-3. PMID 12932731.
  14. ↑ Goehler H, Lalowski M, Stelzl U, Waelter S, Stroedicke M, Worm U, Droege A, Lindenberg KS, Knoblich M, Haenig C, Herbst M, Suopanki J, Scherzinger E, Abraham C, Bauer B, Hasenbank R, Fritzsche A, Ludewig AH, Büssow K, Buessow K, Coleman SH, Gutekunst CA, Landwehrmeyer BG, Lehrach H, Wanker EE (Sep 2004). "A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease". Molecular Cell. 15 (6): 853–65. doi:10.1016/j.molcel.2004.09.016. PMID 15383276.
  15. ↑ Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Wälter S, Tait D, Colicelli J, Lehrach H (Mar 1997). "HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system". Human Molecular Genetics. 6 (3): 487–95. doi:10.1093/hmg/6.3.487. PMID 9147654.
  16. ↑ 16.0 16.1 Liu YF, Deth RC, Devys D (Mar 1997). "SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes". The Journal of Biological Chemistry. 272 (13): 8121–4. doi:10.1074/jbc.272.13.8121. PMID 9079622.
  17. ↑ Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, Wanker EE, Bates GP, Housman DE, Thompson LM (Jun 2000). "The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription". Proceedings of the National Academy of Sciences of the United States of America. 97 (12): 6763–8. doi:10.1073/pnas.100110097. PMC 18731. PMID 10823891.
  18. ↑ Modregger J, DiProspero NA, Charles V, Tagle DA, Plomann M (Oct 2002). "PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington's disease brains". Human Molecular Genetics. 11 (21): 2547–58. doi:10.1093/hmg/11.21.2547. PMID 12354780.
  19. ↑ Sittler A, Wälter S, Wedemeyer N, Hasenbank R, Scherzinger E, Eickhoff H, Bates GP, Lehrach H, Wanker EE (Oct 1998). "SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates". Molecular Cell. 2 (4): 427–36. doi:10.1016/S1097-2765(00)80142-2. PMID 9809064.
  20. ↑ Li SH, Cheng AL, Zhou H, Lam S, Rao M, Li H, Li XJ (Mar 2002). "Interaction of Huntington disease protein with transcriptional activator Sp1". Molecular and Cellular Biology. 22 (5): 1277–87. doi:10.1128/MCB.22.5.1277-1287.2002. PMC 134707. PMID 11839795.
  21. ↑ Kalchman MA, Graham RK, Xia G, Koide HB, Hodgson JG, Graham KC, Goldberg YP, Gietz RD, Pickart CM, Hayden MR (Aug 1996). "Huntingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme". The Journal of Biological Chemistry. 271 (32): 19385–94. doi:10.1074/jbc.271.32.19385. PMID 8702625.
  22. ↑ Liu YF, Dorow D, Marshall J (Jun 2000). "Activation of MLK2-mediated signaling cascades by polyglutamine-expanded huntingtin". The Journal of Biological Chemistry. 275 (25): 19035–40. doi:10.1074/jbc.C000180200. PMID 10801775.
  23. ↑ Hattula K, Peränen J (2000). "FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates cellular morphogenesis". Current Biology. 10 (24): 1603–6. doi:10.1016/S0960-9822(00)00864-2. PMID 11137014.
  24. ↑ 24.0 24.1 24.2 Faber PW, Barnes GT, Srinidhi J, Chen J, Gusella JF, MacDonald ME (Sep 1998). "Huntingtin interacts with a family of WW domain proteins". Human Molecular Genetics. 7 (9): 1463–74. doi:10.1093/hmg/7.9.1463. PMID 9700202.
  25. ↑ Holbert S, Dedeoglu A, Humbert S, Saudou F, Ferrante RJ, Néri C (Mar 2003). "Cdc42-interacting protein 4 binds to huntingtin: neuropathologic and biological evidence for a role in Huntington's disease". Proceedings of the National Academy of Sciences of the United States of America. 100 (5): 2712–7. doi:10.1073/pnas.0437967100. PMC 151406. PMID 12604778.
  26. ↑ Singaraja RR, Hadano S, Metzler M, Givan S, Wellington CL, Warby S, Yanai A, Gutekunst CA, Leavitt BR, Yi H, Fichter K, Gan L, McCutcheon K, Chopra V, Michel J, Hersch SM, Ikeda JE, Hayden MR (Nov 2002). "HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis". Human Molecular Genetics. 11 (23): 2815–28. doi:10.1093/hmg/11.23.2815. PMID 12393793.
  27. ↑ 27.0 27.1 Walker FO (Jan 2007). "Huntington's disease". Lancet. 369 (9557): 218–28. doi:10.1016/S0140-6736(07)60111-1. PMID 17240289.
  28. ↑ 28.0 28.1 Chong SS, Almqvist E, Telenius H, LaTray L, Nichol K, Bourdelat-Parks B, Goldberg YP, Haddad BR, Richards F, Sillence D, Greenberg CR, Ives E, Van den Engh G, Hughes MR, Hayden MR (Feb 1997). "Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses". Human Molecular Genetics. 6 (2): 301–9. doi:10.1093/hmg/6.2.301. PMID 9063751.
  29. ↑ Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP (Aug 1997). "Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation". Cell. 90 (3): 537–48. doi:10.1016/S0092-8674(00)80513-9. PMID 9267033.
  30. ↑ Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (Oct 2004). "Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death". Nature. 431 (7010): 805–10. doi:10.1038/nature02998. PMID 15483602.
  31. ↑ Orr HT (Oct 2004). "Neurodegenerative disease: neuron protection agency". Nature. 431 (7010): 747–8. doi:10.1038/431747a. PMID 15483586.

Further reading

External links

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