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Huntingtin, huntington bank
3IO6, 3IOU, 3LRH, 4FE8, 4FEB, 4FEC, 4FED, 2LD0, 2LD2, 3IO4, 3IOR, 3IOT, 3IOV, 3IOW, 4RAV

IdentifiersAliasesHTT, HD, IT15, huntingtin, LOMARSExternal IDsOMIM: 613004 MGI: 96067 HomoloGene: 1593 GeneCards: HTT
Gene location Human
ChrChromosome 4 human[1]
Band4p163Start3,074,681 bp[1]
End3,243,960 bp[1]
RNA expression pattern
More reference expression data
RefSeq mRNA



RefSeq protein



Location UCSCChr 4: 307 – 324 MbChr 5: 3476 – 3491 MbPubMed search[3][4]Wikidata
1 Gene
  • 2 Protein
    • 21 Function
    • 22 Interactions
  • 3 Mitochondrial dysfunction
  • 4 Clinical significance
  • 5 References
  • 6 Further reading
  • 7 External links
  • 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 163, from base pair 3,074,510 to base pair 3,243,960[9]



    The function of huntingtin is unclear It is essential for development, and absence of huntingtin is lethal in mice[8] The protein has no sequence homology with other proteins and is highly expressed in neurons and testes in humans and rodents[10] 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[11] From immunohistochemistry, electron microscopy, and subcellular fractionation studies of the molecule, it has been found that huntingtin is primarily associated with vesicles and microtubules[12][13] 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[14][15] Huntingtin has also been shown to have a role in the establishment in epithelial polarity through its interaction with RAB11A[16]


    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[17] 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[18][19]

    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[20] 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[21] No Transcription factor
    PACSIN1[22] Yes Endocytosis, actin cytoskeleton
    PSD-95 Yes Postsynaptic Density 95
    RasGAP Not known Ras GTPase activating protein
    SH3GL3[23] Yes Endocytosis
    SIN3A Yes Transcriptional repressor
    Sp1[24] Yes Transcription factor

    Huntingtin has also been shown to interact with:

    • HIP2,[25]
    • MAP3K10,[26]
    • OPTN,[27]
    • PRPF40A,[28]
    • RASA1,[20]
    • SETD2,[28]
    • TRIP10,[29]
    • ZDHHC17[28][30]

    Mitochondrial dysfunction

    Mutant Huntingtin protein plays a key role in mitochondrial dysfunction involving inhibition of mitochondrial electron transport, higher levels of reactive oxygen species and increased oxidative stress[31] Mutant huntingtin protein also promotes oxidative damage to DNA that may contribute to Huntington disease pathology[32]

    Clinical significance

    Main article: Huntington's disease Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats[33]
    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[33] 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[5] However, 36 or more residues produce an erroneous form of Htt, mHtt standing for mutant Htt Reduced penetrance is found in counts 36-39[34]

    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[35] 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[36] 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[37] 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[34]

    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


    1. ^ a b c GRCh38: Ensembl release 89: ENSG00000197386 - Ensembl, May 2017
    2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029104 - Ensembl, May 2017
    3. ^ "Human PubMed Reference:" 
    4. ^ "Mouse PubMed Reference:" 
    5. ^ a b 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:101016/0092-86749390585-E PMID 8458085 
    6. ^ 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:101371/journalpone0103004 PMC 4108396  PMID 25054562 
    7. ^ 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:101212/wnl522392 PMID 9932964 
    8. ^ a b 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:101016/0092-86749590542-1 PMID 7774020 
    9. ^ http://ghrnlmnihgov/gene/HTT
    10. ^ 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:101038/nrn1806 PMID 16288298 
    11. ^ 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:101126/science1059581 PMID 11408619 
    12. ^ 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 
    13. ^ 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:101016/0896-62739590346-1 PMID 7748555 
    14. ^ 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:101006/exnr19986832 PMID 9682010 
    15. ^ 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:101093/hmg/10171807 PMID 11532990 
    16. ^ 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:101371/journalpbio1002142 PMC 4420272  PMID 25942483 
    17. ^ 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:101016/S0968-00040300168-3 PMID 12932731 
    18. ^ 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:101016/jmolcel200409016 PMID 15383276 
    19. ^ 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:101093/hmg/63487 PMID 9147654 
    20. ^ a b 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:101074/jbc272138121 PMID 9079622 
    21. ^ 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:101073/pnas100110097 PMC 18731  PMID 10823891 
    22. ^ 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:101093/hmg/11212547 PMID 12354780 
    23. ^ 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:101016/S1097-27650080142-2 PMID 9809064 
    24. ^ 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:101128/MCB2251277-12872002 PMC 134707  PMID 11839795 
    25. ^ 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:101074/jbc2713219385 PMID 8702625 
    26. ^ 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:101074/jbcC000180200 PMID 10801775 
    27. ^ 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:101016/S0960-98220000864-2 PMID 11137014 
    28. ^ a b c 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:101093/hmg/791463 PMID 9700202 
    29. ^ 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:101073/pnas0437967100 PMC 151406  PMID 12604778 
    30. ^ 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:101093/hmg/11232815 PMID 12393793 
    31. ^ Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L 2017 "Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications" Oxid Med Cell Longev 2017: 2525967 doi:101155/2017/2525967 PMC 5529664  PMID 28785371 
    32. ^ Ayala-Peña S September 2013 "Role of oxidative DNA damage in mitochondrial dysfunction and Huntington's disease pathogenesis" Free Radic Biol Med 62: 102–10 doi:101016/jfreeradbiomed201304017 PMC 3722255  PMID 23602907 
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    34. ^ a b 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:101093/hmg/62301 PMID 9063751 
    35. ^ 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:101016/S0092-86740080513-9 PMID 9267033 
    36. ^ 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:101038/nature02998 PMID 15483602 
    37. ^ Orr HT Oct 2004 "Neurodegenerative disease: neuron protection agency" Nature 431 7010: 747–8 doi:101038/431747a PMID 15483586 

    Further reading

    • Bates G May 2003 "Huntingtin aggregation and toxicity in Huntington's disease" Lancet 361 9369: 1642–4 doi:101016/S0140-67360313304-1 PMID 12747895 
    • Cattaneo E Feb 2003 "Dysfunction of wild-type huntingtin in Huntington disease" News in Physiological Sciences 18: 34–7 doi:101152/nips014102002 PMID 12531930 
    • Gárdián G, Vécsei L Oct 2004 "Huntington's disease: pathomechanism and therapeutic perspectives" Journal of Neural Transmission 111 10-11: 1485–94 doi:101007/s00702-004-0201-4 PMID 15480847 
    • Landles C, Bates GP Oct 2004 "Huntingtin and the molecular pathogenesis of Huntington's disease Fourth in molecular medicine review series" EMBO Reports 5 10: 958–63 doi:101038/sjembor7400250 PMC 1299150  PMID 15459747 
    • Jones AL Jun 1999 "The localization and interactions of huntingtin" Philosophical Transactions of the Royal Society of London Series B, Biological Sciences 354 1386: 1021–7 doi:101098/rstb19990454 PMC 1692601  PMID 10434301 
    • Li SH, Li XJ Oct 2004 "Huntingtin and its role in neuronal degeneration" The Neuroscientist 10 5: 467–75 doi:101177/1073858404266777 PMID 15359012 
    • MacDonald ME, Novelletto A, Lin C, Tagle D, Barnes G, Bates G, Taylor S, Allitto B, Altherr M, Myers R May 1992 "The Huntington's disease candidate region exhibits many different haplotypes" Nature Genetics 1 2: 99–103 doi:101038/ng0592-99 PMID 1302016 
    • MacDonald ME Nov 2003 "Huntingtin: alive and well and working in middle management" Science's STKE 2003 207: pe48 doi:101126/stke2003207pe48 PMID 14600292 
    • Myers RH Apr 2004 "Huntington's disease genetics" NeuroRx 1 2: 255–62 doi:101602/neurorx12255 PMC 534940  PMID 15717026 
    • Rangone H, Humbert S, Saudou F Jul 2004 "Huntington's disease: how does huntingtin, an anti-apoptotic protein, become toxic" Pathologie-Biologie 52 6: 338–42 doi:101016/jpatbio200306004 PMID 15261377 
    • Young AB Feb 2003 "Huntingtin in health and disease" The Journal of Clinical Investigation 111 3: 299–302 doi:101172/JCI17742 PMC 151871  PMID 12569151 

    External links

    • Huntingtin+protein,+human at the US National Library of Medicine Medical Subject Headings MeSH
    • The Huntingtin Protein and Protein Aggregation at HOPES : Huntington's Outreach Project for Education at Stanford
    • The HDA Huntington's Disease Association UK
    • Online Mendelian Inheritance in Man OMIM 143100
    • EntrezGene 3064
    • GeneCard
    • iHOP, huntington bank, huntington bank locations, huntington hospital, huntington learning center, huntington library, huntington online banking, huntington's disease,,

    Huntingtin Information about


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