Huntingtin

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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.

## Contents

* 1 Gene
* 2 Protein
* 2.1 Function
* 2.2 Interactions
* 3 Mitochondrial dysfunction
* 4 Clinical significance
* 5 References
* 6 Further reading
* 7 External links

## Gene

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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

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### Function

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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

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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:

* HIP2,[21]
* MAP3K10,[22]
* OPTN,[23]
* PRPF40A,[24]
* RASA1,[16]
* SETD2,[24]
* TRIP10,[25]
* ZDHHC17.[24][26]

## Mitochondrial dysfunction

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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.[27] Mutant huntingtin protein also promotes oxidative damage to DNA that may contribute to Huntington disease pathology.[28]

## Clinical significance

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Main article: Huntington's disease

Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats[29] 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.[29] 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.[30]

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.[31] 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.[32] 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.[33] 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.[30]

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

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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. ↑ 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: 1–11. doi:10.1155/2017/2525967. PMC 5529664. PMID 28785371.
28. ↑ 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:10.1016/j.freeradbiomed.2013.04.017. PMC 3722255. PMID 23602907.
29. ↑ 29.0 29.1 Walker FO (Jan 2007). "Huntington's disease". Lancet. 369 (9557): 218–28. doi:10.1016/S0140-6736(07)60111-1. PMID 17240289.
30. ↑ 30.0 30.1 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.
31. ↑ 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.
32. ↑ 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.
33. ↑ Orr HT (Oct 2004). "Neurodegenerative disease: neuron protection agency". Nature. 431 (7010): 747–8. doi:10.1038/431747a. PMID 15483586.

## Further reading

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* Kosinski, Christoph M.; Schlangen, Christiane; Gellerich, Frank N.; Gizatullina, Zemfira; Deschauer, Markus; Schiefer, Johannes; Young, Anne B.; Landwehrmeyer, Georg Bernhard; Toyka, Klaus V. (2007-08-15). "Myopathy as a first symptom of Huntington's disease in a Marathon runner". Movement Disorders. 22 (11): 1637–1640. doi:10.1002/mds.21550. ISSN 0885-3185. PMID 17534945.
* Bates G (May 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 (Feb 2003). "Dysfunction of wild-type huntingtin in Huntington disease". News in Physiological Sciences. 18: 34–7. doi:10.1152/nips.01410.2002. 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:10.1007/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:10.1038/sj.embor.7400250. 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:10.1098/rstb.1999.0454. PMC 1692601. PMID 10434301.
* Li SH, Li XJ (Oct 2004). "Huntingtin and its role in neuronal degeneration". The Neuroscientist. 10 (5): 467–75. doi:10.1177/1073858404266777. 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:10.1038/ng0592-99. PMID 1302016.
* MacDonald ME (Nov 2003). "Huntingtin: alive and well and working in middle management". Science's STKE. 2003 (207): pe48. doi:10.1126/stke.2003.207.pe48. PMID 14600292.
* Myers RH (Apr 2004). "Huntington's disease genetics". NeuroRx. 1 (2): 255–62. doi:10.1602/neurorx.1.2.255. 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:10.1016/j.patbio.2003.06.004. PMID 15261377.
* Young AB (Feb 2003). "Huntingtin in health and disease". The Journal of Clinical Investigation. 111 (3): 299–302. doi:10.1172/JCI17742. PMC 151871. PMID 12569151.

## External links

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* 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