Huntingtin

The huntingtin is_associated_with::gene, also called the HTT or HD (Huntington disease) gene, is the IT15 ("interesting transcript 15") gene, which codes for a is_associated_with::protein called the huntingtin protein. The gene and its product are under heavy investigation as part of is_associated_with::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 is_associated_with::glutamine residues present in the protein. In its is_associated_with::wild-type (normal) form, it contains 6-35 is_associated_with::glutamine residues. However, in individuals affected by is_associated_with::Huntington's disease (an is_associated_with::autosomal dominant is_associated_with::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 is_associated_with::nerve cells. Within cells, huntingtin may be involved in signaling, transporting materials, binding proteins and other structures, and protecting against programmed cell death (is_associated_with::apoptosis). The huntingtin protein is required for normal development before is_associated_with::birth. It is expressed in many tissues in the body, with the highest levels of expression seen in the brain.

Gene
The 5' end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid is_associated_with::glutamine, that is repeated multiple times. This region is called a is_associated_with::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 is_associated_with::base pair 3,113,411 to base pair 3,282,655.

Function
The function of huntingtin is unclear. It is essential for development, and absence of huntingtin is lethal in mice. The protein has no is_associated_with::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 is_associated_with::immunohistochemistry, is_associated_with::electron microscopy, and is_associated_with::subcellular fractionation studies of the molecule, it has been found that huntingtin is primarily associated with vesicles and is_associated_with::microtubules. These appear to indicate a functional role in cytoskeletal anchoring or transport of is_associated_with::mitochondria. The Htt protein is involved in vesicle trafficking as it interacts with HIP1, a is_associated_with::clathrin-binding protein, to mediate is_associated_with::endocytosis, the absorption of materials into a cell. Huntingtin has also been shown to have a role in the establishment in is_associated_with::epithelial polarity through its interaction with is_associated_with::RAB11A.

Interactions
Huntingtin has been found to interact directly with at least 19 other is_associated_with::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 is_associated_with::huntingtin-associated protein 1 (HAP1) and huntingtin interacting protein 1 (HIP1), these were typically found using is_associated_with::two-hybrid screening and confirmed using is_associated_with::immunoprecipitation.

Huntingtin has also been shown to interact with:


 * is_associated_with::HIP2,
 * is_associated_with::MAP3K10,
 * OPTN,
 * is_associated_with::PRPF40A,
 * RASA1,
 * is_associated_with::SETD2,
 * is_associated_with::TRIP10,
 * is_associated_with::ZDHHC17.

Clinical significance
is_associated_with::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. These expanded repeats lead to production of a huntingtin protein that contains an abnormally long is_associated_with::polyglutamine tract at the N-terminus. This makes it part of a class of neurodegenerative disorders known as is_associated_with::trinucleotide repeat disorders or polyglutamine disorders. The key sequence which is found in Huntington's disease is a trinucleotide repeat expansion of is_associated_with::glutamine residues beginning at the 18th amino acid. In unaffected individuals, this contains between 9 and 35 glutamine residues with no adverse effects. However, 36 or more residues produce an erroneous form of Htt, mHtt (standing for mutant Htt). Reduced penetrance is found in counts 36-39.

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. 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. 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. This process is particularly likely to occur in the is_associated_with::striatum (a part of the brain that coordinates movement) primarily, and the is_associated_with::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.

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.