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Gene Review

HTT  -  huntingtin

Homo sapiens

Synonyms: HD, HD protein, Huntingtin, Huntington disease protein, IT15

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Disease relevance of HD


Psychiatry related information on HD


High impact information on HD


Chemical compound and disease context of HD


Biological context of HD

  • Our results show that huntingtin is cleaved by cysteine proteases and suggest that HD might be a disorder of inappropriate apoptosis [18].
  • Pathogenesis in HD seems to involve the formation of neuronal intranuclear inclusions and the abnormal regulation of transcription and signal transduction [3].
  • Using spectrophotometric assays in postmortem brain tissue, we found evidence of impaired oxidative phosphorylation enzyme activities restricted to the basal ganglia in HD brain, while enzyme activities were unaltered in three regions relatively spared by HD pathology (frontal cortex, parietal cortex, and cerebellum) [19].
  • A key strategy for understanding HD pathology is to identify signaling cascades initiated by mutant Htt that lead to neuronal cell death and dysfunction [20].
  • These findings reveal a singular, new subcellular phenotype in HD cells [21].

Anatomical context of HD


Associations of HD with chemical compounds


Physical interactions of HD


Enzymatic interactions of HD


Co-localisations of HD


Regulatory relationships of HD

  • In the striatum, huntingtin is expressed in 75% of neurons containing BDNF [35].
  • When a YFP-tagged mutant truncated huntingtin construct was transiently transfected into cells that express no detectable tTG due to stable transfection with a tTG antisense construct, there was extensive aggregate formation [36].
  • However, in addition to CBP recruitment, we show here that CBP ubiquitylation and degradation can be selectively enhanced by polyQ-expanded htt [37].
  • The serum- and glucocorticoid-induced kinase SGK inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin [16].
  • In our previous studies, we found that expression of polyglutamine-expanded huntingtin in HN33 cells induced sensitization of N-methyl-D-aspartate (NMDA) receptors (Sun, Y., Savinainen, A., and Liu, Y. F. (2001) J. Biol. Chem. 276, 24713-24718) [31].

Other interactions of HD

  • Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract [18].
  • SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates [29].
  • Marked CIP4 overexpression also was observed in Western blot from human HD brain striatum [3].
  • Using the yeast two-hybrid system, we have isolated a novel htt interacting protein, HIP14 [38].
  • Furthermore, this interaction is repeat-length-dependent and is enhanced with mutant huntingtin, possibly causing the sequestration of PACSIN 1 [24].

Analytical, diagnostic and therapeutic context of HD


  1. A huntingtin-associated protein enriched in brain with implications for pathology. Li, X.J., Li, S.H., Sharp, A.H., Nucifora, F.C., Schilling, G., Lanahan, A., Worley, P., Snyder, S.H., Ross, C.A. Nature (1995) [Pubmed]
  2. Arfaptin 2 regulates the aggregation of mutant huntingtin protein. Peters, P.J., Ning, K., Palacios, F., Boshans, R.L., Kazantsev, A., Thompson, L.M., Woodman, B., Bates, G.P., D'Souza-Schorey, C. Nat. Cell Biol. (2002) [Pubmed]
  3. Cdc42-interacting protein 4 binds to huntingtin: neuropathologic and biological evidence for a role in Huntington's disease. Holbert, S., Dedeoglu, A., Humbert, S., Saudou, F., Ferrante, R.J., Néri, C. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. Dysregulation of C/EBP{alpha} by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease. Chiang, M.C., Chen, H.M., Lee, Y.H., Chang, H.H., Wu, Y.C., Soong, B.W., Chen, C.M., Wu, Y.R., Liu, C.S., Niu, D.M., Wu, J.Y., Chen, Y.T., Chern, Y. Hum. Mol. Genet. (2007) [Pubmed]
  5. Huntingtin-associated protein (HAP1): discrete neuronal localizations in the brain resemble those of neuronal nitric oxide synthase. Li, X.J., Sharp, A.H., Li, S.H., Dawson, T.M., Snyder, S.H., Ross, C.A. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  6. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Nucifora , F.C., Sasaki, M., Peters, M.F., Huang, H., Cooper, J.K., Yamada, M., Takahashi, H., Tsuji, S., Troncoso, J., Dawson, V.L., Dawson, T.M., Ross, C.A. Science (2001) [Pubmed]
  7. Early onset autosomal dominant dementia with ataxia, extrapyramidal features, and epilepsy. Filla, A., De Michele, G., Cocozza, S., Patrignani, A., Volpe, G., Castaldo, I., Ruggiero, G., Bonavita, V., Masters, C., Casari, G., Bruni, A. Neurology (2002) [Pubmed]
  8. Cognitive manifestations of Huntington disease in relation to genetic structure and clinical onset. Jason, G.W., Suchowersky, O., Pajurkova, E.M., Graham, L., Klimek, M.L., Garber, A.T., Poirier-Heine, D. Arch. Neurol. (1997) [Pubmed]
  9. SUMO wrestling with type 1 diabetes. Li, M., Guo, D., Isales, C.M., Eizirik, D.L., Atkinson, M., She, J.X., Wang, C.Y. J. Mol. Med. (2005) [Pubmed]
  10. Huntington's disease genetics. Myers, R.H. NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics. (2004) [Pubmed]
  11. Nucleocytoplasmic trafficking and transcription effects of huntingtin in Huntington's disease. Truant, R., Atwal, R.S., Burtnik, A. Prog. Neurobiol. (2007) [Pubmed]
  12. Transcriptional Repression of PGC-1alpha by Mutant Huntingtin Leads to Mitochondrial Dysfunction and Neurodegeneration. Cui, L., Jeong, H., Borovecki, F., Parkhurst, C.N., Tanese, N., Krainc, D. Cell (2006) [Pubmed]
  13. A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Giorgini, F., Guidetti, P., Nguyen, Q., Bennett, S.C., Muchowski, P.J. Nat. Genet. (2005) [Pubmed]
  14. Huntingtin-associated protein 1 (HAP1) binds to a Trio-like polypeptide, with a rac1 guanine nucleotide exchange factor domain. Colomer, V., Engelender, S., Sharp, A.H., Duan, K., Cooper, J.K., Lanahan, A., Lyford, G., Worley, P., Ross, C.A. Hum. Mol. Genet. (1997) [Pubmed]
  15. The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Humbert, S., Bryson, E.A., Cordelières, F.P., Connors, N.C., Datta, S.R., Finkbeiner, S., Greenberg, M.E., Saudou, F. Dev. Cell (2002) [Pubmed]
  16. The serum- and glucocorticoid-induced kinase SGK inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin. Rangone, H., Poizat, G., Troncoso, J., Ross, C.A., MacDonald, M.E., Saudou, F., Humbert, S. Eur. J. Neurosci. (2004) [Pubmed]
  17. Hyperhomocysteinaemia in treated patients with Huntington's disease homocysteine in HD. Andrich, J., Saft, C., Arz, A., Schneider, B., Agelink, M.W., Kraus, P.H., Kuhn, W., Müller, T. Mov. Disord. (2004) [Pubmed]
  18. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Goldberg, Y.P., Nicholson, D.W., Rasper, D.M., Kalchman, M.A., Koide, H.B., Graham, R.K., Bromm, M., Kazemi-Esfarjani, P., Thornberry, N.A., Vaillancourt, J.P., Hayden, M.R. Nat. Genet. (1996) [Pubmed]
  19. Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia. Browne, S.E., Bowling, A.C., MacGarvey, U., Baik, M.J., Berger, S.C., Muqit, M.M., Bird, E.D., Beal, M.F. Ann. Neurol. (1997) [Pubmed]
  20. Mechanisms for neuronal cell death and dysfunction in Huntington's disease: pathological cross-talk between the nucleus and the mitochondria? Sawa, A. J. Mol. Med. (2001) [Pubmed]
  21. Alteration of nuclear glyceraldehyde-3-phosphate dehydrogenase structure in Huntington's disease fibroblasts. Mazzola, J.L., Sirover, M.A. Brain Res. Mol. Brain Res. (2002) [Pubmed]
  22. IRS-PCR-based genetic mapping of the huntingtin interacting protein gene (HIP1) on mouse chromosome 5. Himmelbauer, H., Wedemeyer, N., Haaf, T., Wanker, E.E., Schalkwyk, L.C., Lehrach, H. Mamm. Genome (1998) [Pubmed]
  23. Glyceraldehyde 3-phosphate dehydrogenase abnormality in metabolically stressed Huntington disease fibroblasts. Cooper, A.J., Sheu, K.F., Burke, J.R., Strittmatter, W.J., Blass, J.P. Dev. Neurosci. (1998) [Pubmed]
  24. PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington's disease brains. Modregger, J., DiProspero, N.A., Charles, V., Tagle, D.A., Plomann, M. Hum. Mol. Genet. (2002) [Pubmed]
  25. Tissue transglutaminase selectively modifies proteins associated with truncated mutant huntingtin in intact cells. Chun, W., Lesort, M., Tucholski, J., Faber, P.W., MacDonald, M.E., Ross, C.A., Johnson, G.V. Neurobiol. Dis. (2001) [Pubmed]
  26. Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins. Huang, C.C., Faber, P.W., Persichetti, F., Mittal, V., Vonsattel, J.P., MacDonald, M.E., Gusella, J.F. Somat. Cell Mol. Genet. (1998) [Pubmed]
  27. Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin. Engelender, S., Sharp, A.H., Colomer, V., Tokito, M.K., Lanahan, A., Worley, P., Holzbaur, E.L., Ross, C.A. Hum. Mol. Genet. (1997) [Pubmed]
  28. Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo. Warby, S.C., Chan, E.Y., Metzler, M., Gan, L., Singaraja, R.R., Crocker, S.F., Robertson, H.A., Hayden, M.R. Hum. Mol. Genet. (2005) [Pubmed]
  29. SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates. Sittler, A., Wälter, S., Wedemeyer, N., Hasenbank, R., Scherzinger, E., Eickhoff, H., Bates, G.P., Lehrach, H., Wanker, E.E. Mol. Cell (1998) [Pubmed]
  30. Toward understanding the molecular pathology of Huntington's disease. Wellington, C.L., Brinkman, R.R., O'Kusky, J.R., Hayden, M.R. Brain Pathol. (1997) [Pubmed]
  31. Expression of polyglutamine-expanded huntingtin induces tyrosine phosphorylation of N-methyl-D-aspartate receptors. Song, C., Zhang, Y., Parsons, C.G., Liu, Y.F. J. Biol. Chem. (2003) [Pubmed]
  32. Neurofilament and neural cell adhesion molecule immunocytochemistry of Huntington's disease striatum. Nihei, K., Kowall, N.W. Ann. Neurol. (1992) [Pubmed]
  33. Terminal deletion of chromosome 4p (4p16.3) shows a breakpoint between loci linked to Huntington disease. Ikonen, E., Salo, A., Somer, M., Somer, H., Pääkkönen, L., Peltonen, L. Am. J. Med. Genet. (1992) [Pubmed]
  34. Mutant huntingtin protein: a substrate for transglutaminase 1, 2, and 3. Zainelli, G.M., Dudek, N.L., Ross, C.A., Kim, S.Y., Muma, N.A. J. Neuropathol. Exp. Neurol. (2005) [Pubmed]
  35. Co-localization of brain-derived neurotrophic factor (BDNF) and wild-type huntingtin in normal and quinolinic acid-lesioned rat brain. Fusco, F.R., Zuccato, C., Tartari, M., Martorana, A., De March, Z., Giampà, C., Cattaneo, E., Bernardi, G. Eur. J. Neurosci. (2003) [Pubmed]
  36. Tissue transglutaminase does not contribute to the formation of mutant huntingtin aggregates. Chun, W., Lesort, M., Tucholski, J., Ross, C.A., Johnson, G.V. J. Cell Biol. (2001) [Pubmed]
  37. Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein. Jiang, H., Nucifora, F.C., Ross, C.A., DeFranco, D.B. Hum. Mol. Genet. (2003) [Pubmed]
  38. HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis. Singaraja, R.R., Hadano, S., Metzler, M., Givan, S., Wellington, C.L., Warby, S., Yanai, A., Gutekunst, C.A., Leavitt, B.R., Yi, H., Fichter, K., Gan, L., McCutcheon, K., Chopra, V., Michel, J., Hersch, S.M., Ikeda, J.E., Hayden, M.R. Hum. Mol. Genet. (2002) [Pubmed]
  39. The cellular and subcellular localization of huntingtin-associated protein 1 (HAP1): comparison with huntingtin in rat and human. Gutekunst, C.A., Li, S.H., Yi, H., Ferrante, R.J., Li, X.J., Hersch, S.M. J. Neurosci. (1998) [Pubmed]
  40. Exclusion of mutations in the PRNP, JPH3, TBP, ATN1, CREBBP, POU3F2 and FTL genes as a cause of disease in Portuguese patients with a Huntington-like phenotype. Costa, M.d.o. .C., Teixeira-Castro, A., Constante, M., Magalhães, M., Magalhães, P., Cerqueira, J., Vale, J., Passão, V., Barbosa, C., Robalo, C., Coutinho, P., Barros, J., Santos, M.M., Sequeiros, J., Maciel, P. J. Hum. Genet. (2006) [Pubmed]
  41. Interaction of huntingtin-associated protein with dynactin P150Glued. Li, S.H., Gutekunst, C.A., Hersch, S.M., Li, X.J. J. Neurosci. (1998) [Pubmed]
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