Crystallographic structure of the N-terminal region of the human Huntingtin protein with an artificially attached Maltose-Binding protein used for crystallographic purposes.
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
The huntingtin gene, also called HTT or HD (Huntington disease) gene, is the IT15 ("interesting transcript 15") gene which codes for a protein called the huntingtin protein. The gene and its product are under heavy investigation as part of Huntington's disease clinical research.
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 greater than 36 glutamine residues (highest reported repeat length is about 250). 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. It is expressed in many tissues in the body, with the highest levels of expression seen in the brain.
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 function of huntingtin is unclear. It is essential for development, and absence of huntingtin is lethal in mice. The protein has no sequence homology with other proteins and is highly expressed in neurons and testes in humans and rodents. 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. From immunohistochemistry, electron microscopy, and subcellular fractionation studies of the molecule, it has been found that huntingtin is primarily associated with vesicles and microtubules. 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 absorption of materials into a cell.
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). 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.
|Interacting Protein||PolyQ length dependence||Function|
|CBP||Yes||Transcriptional co-activator with acetyltransferase activity|
|CIP4||Yes||cdc42-dependent signal transduction|
|FIP2||Not known||Cell morphogenesis|
|Grb2||Not known||Growth factor receptor binding protein|
|N-CoR||Yes||Nuclear receptor co-repressor|
|NF-κB||Not known||Transcription factor|
|PACSIN1||Yes||Endocytosis, actin cytoskeleton|
|PSS-95||Yes||Synaptic scaffolding protein|
|RasGAP||Not known||Ras GTPase activating protein|
Huntingtin has also been shown to interact with:
Clinical significance 
Huntington's disease (HD) is caused by a mutation in the huntingtin gene, where the CAG repeats more than 36 times and is unstable. 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. However, 36 or more residues produce an erroneous form of Htt, mHtt (standing for mutant Htt). Reduced penetrance is found in counts 36-39.
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. 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. 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. 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).
|Repeat count||Classification||Disease status|
|36–40||Reduced penetrance||+/- Affected|
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.
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.
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- Cattaneo E, Zuccato C, Tartari M (December 2005). "Normal huntingtin function: an alternative approach to Huntington's disease". Nature Reviews. Neuroscience 6 (12): 919–30. doi:10.1038/nrn1806. PMID 16288298.
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- Velier J, Kim M, Schwarz C, Kim TW, Sapp E, Chase K, Aronin N, DiFiglia M (July 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.
- Waelter S, Scherzinger E, Hasenbank R, Nordhoff E, Lurz R, Goehler H, Gauss C, Sathasivam K, Bates GP, Lehrach H, Wanker EE (August 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.
- Harjes P, Wanker EE (August 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.
- Goehler H, Lalowski M, Stelzl U, et al. (September 2004). "A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease". Mol. Cell 15 (6): 853–65. doi:10.1016/j.molcel.2004.09.016. PMID 15383276. Retrieved 2009-04-27.
- Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Walter S, et al. (March 1997). "HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system". Hum. Mol. Genet. 6 (3): 487–95. doi:10.1093/hmg/6.3.487. PMID 9147654.
- Liu, Y F; Deth R C, Devys D (March 1997). "SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes". J. Biol. Chem. (UNITED STATES) 272 (13): 8121–4. doi:10.1074/jbc.272.13.8121. ISSN 0021-9258. PMID 9079622.
- Steffan, J S; Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu Y Z, Gohler H, Wanker E E, Bates G P, Housman D E, Thompson L M (June 2000). "The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 97 (12): 6763–8. doi:10.1073/pnas.100110097. ISSN 0027-8424. PMC 18731. PMID 10823891.
- Modregger, January; DiProspero Nicholas A, Charles Vinod, Tagle Danilo A, Plomann Markus (October 2002). "PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington's disease brains". Hum. Mol. Genet. (England) 11 (21): 2547–58. doi:10.1093/hmg/11.21.2547. ISSN 0964-6906. PMID 12354780.
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- Liu YF, Dorow D, Marshall J (June 2000). "Activation of MLK2-mediated signaling cascades by polyglutamine-expanded huntingtin". J. Biol. Chem. 275 (25): 19035–40. doi:10.1074/jbc.C000180200. PMID 10801775.
- Hattula K, Peränen J (2000). "FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates cellular morphogenesis". Curr. Biol. 10 (24): 1603–6. doi:10.1016/S0960-9822(00)00864-2. PMID 11137014.
- Faber PW, Barnes GT, Srinidhi J, Chen J, Gusella JF, MacDonald ME (September 1998). "Huntingtin interacts with a family of WW domain proteins". Hum. Mol. Genet. 7 (9): 1463–74. doi:10.1093/hmg/7.9.1463. PMID 9700202.
- Holbert S, Dedeoglu A, Humbert S, Saudou F, Ferrante RJ, Néri C (March 2003). "Cdc42-interacting protein 4 binds to huntingtin: Neuropathologic and biological evidence for a role in Huntington's disease". Proc. Natl. Acad. Sci. U.S.A. 100 (5): 2712–7. doi:10.1073/pnas.0437967100. PMC 151406. PMID 12604778.
- 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 (November 2002). "HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis". Hum. Mol. Genet. 11 (23): 2815–28. doi:10.1093/hmg/11.23.2815. PMID 12393793.
- Walker FO (2007). "Huntington's disease". Lancet 369 (9557): 218–28. doi:10.1016/S0140-6736(07)60111-1. PMID 17240289.
- Huntington's Disease Collaborative Research Group (1993). "A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes". Cell 72 (6): 971–983. doi:10.1016/0092-8674(93)90585-E. PMID 8458085.
- 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 (February 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. PMID 9063751.
- Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP (August 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.
- Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (2004). "Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death". Nature 431 (7010): 805–810. doi:10.1038/nature02998. PMID 15483602.
- Orr HT (October 2004). "Neurodegenerative disease: neuron protection agency". Nature 431 (7010): 747–8. doi:10.1038/431747a. PMID 15483586.
Further reading 
- Bates G (2003). "Huntingtin aggregation and toxicity in Huntington's disease". Lancet 361 (9369): 1642–4. doi:10.1016/S0140-6736(03)13304-1. PMID 12747895.
- Cattaneo E (2003). "Dysfunction of wild-type huntingtin in Huntington disease". News Physiol Sci 18: 34–7. PMID 12531930.
- Gardian G, Vecsei L (2004). "Huntington's disease: pathomechanism and therapeutic perspectives". J Neural Transm 111 (10–11): 1485–94. doi:10.1007/s00702-004-0201-4. PMID 15480847.
- Landles C, Bates GP (2004). "Huntingtin and the molecular pathogenesis of Huntington's disease". EMBO Rep 5 (10): 958–63. doi:10.1038/sj.embor.7400250. PMC 1299150. PMID 15459747.
- Jones AL (1999). "The localization and interactions of huntingtin". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 354 (1386): 1021–7. doi:10.1098/rstb.1999.0454. PMC 1692601. PMID 10434301.
- Li SH, Li XJ (2004). "Huntingtin and its role in neuronal degeneration". Neuroscientist 10 (5): 467–75. doi:10.1177/1073858404266777. PMID 15359012.
- MacDonald ME, Novelletto A, Lin C, et al. (1993). "The Huntington's disease candidate region exhibits many different haplotypes". Nat. Genet. 1 (2): 99–103. doi:10.1038/ng0592-99. PMID 1302016.
- MacDonald ME (2003). "Huntingtin: alive and well and working in middle management". Sci STKE 2003 (207): pe48. doi:10.1126/stke.2003.207.pe48. PMID 14600292.
- Myers RH (2005). "Huntington's Disease Genetics". NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics 1 (2): 255–62. doi:10.1602/neurorx.1.2.255. PMC 534940. PMID 15717026.
- Rangone H, Humbert S, Saudou F (2004). "Huntington's disease: how does huntingtin, an anti-apoptotic protein, become toxic?". Pathol Biol (Paris) 52 (6): 338–42. doi:10.1016/j.patbio.2003.06.004. PMID 15261377.
- Young AB (2003). "Huntingtin in health and disease". J Clin Invest 111 (3): 299–302. doi:10.1172/JCI17742. PMC 151871. PMID 12569151.
- 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