Huntingtin
| Huntingtin (Huntington disease) | |||||||||||
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| Symbols | HD ; HTT; IT15 | ||||||||||
| External IDs | Template:OMIM5 Template:MGI HomoloGene: 1593 | ||||||||||
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| Species | Human | Mouse | |||||||||
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Huntingtin (Htt) is the protein coded by the 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
The function of Huntingtin is unclear. It is essential for development and absence of huntingtin is lethal in mice.[1] The protein has no sequence homology with other proteins and is highly expressed in neurons and testes in humans and rodents.[2] 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.[3]
From immunohistochemistry, electron microscopy, subcellular fractionation studies of the molecule, it has been found that Huntingtin is primarily associated with vesicles and microtubules.[4][5].These appear to indicate a functional role in cytoskeletal anchoring or transport of mitochondria.
Huntingtin has also been found to interact with a number of proteins. One such protein is the Huntingtin Interacting Protein I (HIP-I/Hip-1).[6] Unfortunately the actions mediated via these interactions of huntingtin with the complementary interacting proteins are not fully understood.
Abnormal huntingtin (mHtt)
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.[7] 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
Huntingtin was identified in 1993.[8]
References
- ↑ 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.
- ↑ Cattaneo E, Zuccato C, Tartari M (2005 Dec). "Normal huntingtin function: an alternative approach to Huntington's disease". Nature Reviews Neuroscience. 6: 919–930. doi:10.1038/nrn1806. Check date values in:
|date=(help) - ↑ Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D; et al. (2001 Jul 20). "Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease". Science. 293 (5529): 445–6. Check date values in:
|date=(help) - ↑ 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.
- ↑ DiFiglia M; et al. (1995). "Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons". Neuron. 14: 1075–1081.
- ↑ Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Walter S; et al. (1997 Mar). "HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system". Hum. Mol. Genet. 6 (3): 487–95. Check date values in:
|date=(help) - ↑ 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.
- ↑ "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. PMID 8458085.
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.
See also
External links
- Huntingtin+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)