Huntingtin protein

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LocusChr. 4 p16.3

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Huntingtin (Htt) is the protein coded by the gene, huntingtin, identified in 1993.[1] It is variable in its structure as there are many polymorphisms of the gene which 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 between 36-155 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.


The function of Huntingtin is unclear. It is essential for development and absence of huntingtin is lethal in mice.[2] The protein has no sequence homology with other proteins and is highly expressed in neurons and testes in humans and rodents.[3] It has however been experimentally demonstrated that Huntingtin acts as a transcription factor in upregulating the expression of Brain Derived Neurotrophic Factor (BDNF). In the deficient protein, there is suppression of this transcription regulatory function of Huntingtin and hence underexpression of BDNF.[4]From immunohistochemistry, electron microscopy, subcellular fractionation studies of the molecule, it has been found that Huntingtin is primarily associated with vesicles and microtubules.[5][6].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 HIT1, a clathrin binding protein, to mediate endocytosis, the absorption of materials into a cell.[7][8]


Huntingtin has been found to interact with a number of proteins,such as Huntingtin-associated protein 1 (HAP1) and Huntingtin Interacting Protein 1 (HIP1).[9].

Interacting Protein PolyQ length dependence Function
alpha-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 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
NFκB Not known Transcription Factor
p53 No Transcription factor
PACSIN1 Yes Endocytosis, actin cytoskeleton
PSS-95 Yes Synaptic scaffolding protein
RasGAP Not known Ras GTPase activating protein
SH3GL3 Yes Endocytosis
Sin3a Yes Transcriptional repressor
Sp1 Yes Transcription factor


Abnormal huntingtin (mHtt)

The key sequence which is found in Huntington's disease (HD) 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.[11] However, 36 or more residues produce an erroneous form of Htt, mHtt (standing for mutant Htt). Reduced penetrance is found in counts 36-39.[12]

Effect classification repeat count
unnaffected normal < 27
intermediate 27 - 35
affected Reduced Penetrance 36 - 39
Full Penetrance > 39


  1. "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. 1993. doi:10.1016/0092-8674(93)90585-E. PMID 8458085.
  2. Nasir J, Floresco S; et al. (1995). "Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes". Cell. 81: 811–823. doi:10.1016/0092-8674(95)90542-1.
  3. Cattaneo E, Zuccato C, Tartari M (2005). "Normal huntingtin function: an alternative approach to Huntington's disease". Nature Reviews Neuroscience. 6: 919–930. doi:10.1038/nrn1806. Unknown parameter |month= ignored (help)
  4. Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D; et al. (2001-07-20). "Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease". Science. 293 (5529): 445–6.
  5. Hoffner G, Kahlem P, Djian P (2002). "Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with β-tubulin: relevance to Huntington's disease". J Cell Sci. 115: 941–948.
  6. DiFiglia M; et al. (1995). "Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons". Neuron. 14: 1075–1081. doi:10.1016/0896-6273(95)90346-1.
  7. Velier J, Kim M, Schwarz C; et al. (1998). "Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways". Exp. Neurol. 152 (1): 34–40. doi:10.1006/exnr.1998.6832. PMID 9682010.
  8. Waelter S, Scherzinger E, Hasenbank R; et al. (2001). "The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis". Hum. Mol. Genet. 10 (17): 1807–17. doi:10.1093/hmg/10.17.1807. PMID 11532990.
  9. Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Walter S; et al. (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. Unknown parameter |month= ignored (help)
  10. Harjes, P. and E. E. Wanker (2003). "The hunt for huntingtin function: interaction partners tell many different stories." Trends Biochem Sci 28(8): 425-33.
  11. 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: 971–983. doi:10.1016/0092-8674(93)90585-E.
  12. Chong, S.S., Almqvist, E., Telenius, H., LaTray, L., Nichol, K., Bourdelat-Parks, B., Goldberg, Y.P., Haddad, B.R., Richards, F., Sillence, D., Greenberg, C.R., Ives, E., Van den Engh, G., Hughes, M.R., and Hayden, M.R. (1997). Contribution of DNA sequence and CAG size to mutation frquences of intermediate alleles for Huntington Disease: Evidence from single sperm analyses. Human Molecular Genetics 6:302-309

Further reading

  • 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.
  • 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. PMID 10434301.
  • Young AB (2003). "Huntingtin in health and disease". J. Clin. Invest. 111 (3): 299–302. PMID 12569151.
  • Rangone H, Humbert S, Saudou F (2004). "Huntington's disease: how does huntingtin, an anti-apoptotic protein, become toxic?". Pathol. Biol. 52 (6): 338–42. doi:10.1016/j.patbio.2003.06.004. PMID 15261377.
  • Li SH, Li XJ (2005). "Huntingtin and its role in neuronal degeneration". The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 10 (5): 467–75. doi:10.1177/1073858404266777. PMID 15359012.
  • Myers RH (2005). "Huntington's disease genetics". NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics. 1 (2): 255–62. PMID 15717026.

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