Huntingtin

3IO6, 3IOU, 3LRH, 4FE8, 4FEB, 4FEC, 4FED, 2LD0, 2LD2, 3IO4, 3IOR, 3IOT, 3IOV, 3IOW, 4RAV306415194ENSG00000197386ENSMUSG00000029104P42858P42859NM_002111NM_010414NP_002102NP_034544The 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. 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. 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. 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. 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). 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 or may not 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 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. 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 trafficking of materials into a cell. Huntingtin has also been shown to have a role in the establishment in epithelial polarity through its interaction with RAB11A. 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. Huntingtin has also been shown to interact with: 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. Mutant huntingtin protein also promotes oxidative damage to DNA that may contribute to Huntington disease pathology.