Huntingtin


The huntingtin gene, also called the HTT or HD gene, is the IT15 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 form, it contains 6-35 glutamine residues. However, in individuals affected by Huntington's disease, it contains more than 36 glutamine residues. 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. 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.

Gene

The 5' end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine, 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 arm of chromosome 4 at position 16.3, from base pair 3,074,510 to base pair 3,243,960.

Protein

Function

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 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.

Interactions

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. Over 100 interacting proteins have been found, such as huntingtin-associated protein 1 and huntingtin interacting protein 1, these were typically found using two-hybrid screening and confirmed using immunoprecipitation.
Interacting ProteinPolyQ length dependenceFunction
α-adaptin C/HYPJYesEndocytosis
Akt/PKBNoKinase
CBPYesTranscriptional co-activator with acetyltransferase activity
CA150NoTranscriptional activator
CIP4Yescdc42-dependent signal transduction
CtBPYesTranscription factor
FIP2Not knownCell morphogenesis
Grb2Not knownGrowth factor receptor binding protein
HAP1YesMembrane trafficking
HAP40Not knownUnknown
HIP1YesEndocytosis, proapoptotic
HIP14/HYP-HYesTrafficking, endocytosis
N-CoRYesNuclear receptor co-repressor
NF-κBNot knownTranscription factor
p53NoTranscription factor
PACSIN1YesEndocytosis, actin cytoskeleton
PSD-95YesPostsynaptic Density 95
RasGAPNot knownRas GTPase activating protein
SH3GL3YesEndocytosis
SIN3AYesTranscriptional repressor
Sp1YesTranscription factor

Huntingtin has also been shown to interact with:
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.

Clinical significance

Repeat countClassificationDisease status
<26NormalUnaffected
27–35IntermediateUnaffected
36–40Reduced penetrance+/- Affected
>40Full penetranceAffected

Huntington's disease is caused by a mutated form of the huntingtin gene, where excessive CAG repeats result in formation of an unstable protein. These expanded repeats lead to production of a huntingtin protein that contains an abnormally long polyglutamine tract at the N-terminus. This makes it part of a class of neurodegenerative disorders known as trinucleotide repeat disorders or polyglutamine disorders. The key sequence which is found in Huntington's disease 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. However, 36 or more residues produce an erroneous form of Htt, "mHtt". 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, inside nerve cells, and may attract other, normal proteins into the clumps. The characteristic presence of these clumps in patients was thought to contribute to the development of Huntington disease. However, later research raised questions about the role of the inclusions by showing the presence of visible NIIs extended the life of neurons and acted to reduce intracellular mutant huntingtin in neighboring neurons. One confounding factor is that different types of aggregates are now recognised to be formed by the mutant protein, including protein deposits that are too small to be recognised as visible deposits in the above mentioned studies. The likelihood of neuronal death remains difficult to predict. Likely multiple factors are important, including: the length of CAG repeats in the Huntingtin gene and the neuron's exposure to diffuse intracellular mutant huntingtin protein. NIIs can be helpful as a coping mechanism—and not simply a pathogenic mechanism—to stem neuronal death by decreasing the amount of diffuse huntingtin. This process is particularly likely to occur in the striatum primarily, and the frontal cortex.
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 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.