Huntingtin

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HTT
Available structures PDB Ortholog search: PDBe RCSB

Identifiers
Aliases	HTT, HD, IT15, huntingtin, LOMARS
External IDs	OMIM: 613004 MGI: 96067 HomoloGene: 1593 GeneCards: HTT

Gene location (Human) Chr. Chromosome 4 (human) Band 4p16.3 Start 3,041,422 bp End 3,243,960 bp

RNA expression pattern More reference expression data

Gene ontology
Orthologs
Species	Human	Mouse
Entrez	3064	15194
Ensembl	ENSG00000197386	ENSMUSG00000029104
UniProt	P42858	P42859
RefSeq (mRNA)	NM_002111	NM_010414
RefSeq (protein)	NP_002102	NP_034544
Location (UCSC)	Chr 4: 3.04 – 3.24 Mb	Chr 5: 34.76 – 34.91 Mb

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.

Gene

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.

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 (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.

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 (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.

Interacting Protein	PolyQ length dependence	Function
α-adaptin C/HYPJ	Yes	Endocytosis
Akt/PKB	No	Kinase
CBP	Yes	Transcriptional co-activator with acetyltransferase activity
CA150	No	Transcriptional activator
CIP4	Yes	cdc42-dependent signal transduction
CtBP	Yes	Transcription factor
FIP2	Not known	Cell morphogenesis
Grb2	Not known	Growth factor receptor binding protein
HAP1	Yes	Membrane trafficking
HAP40	Not known	Unknown
HIP1	Yes	Endocytosis, proapoptotic
HIP14/HYP-H	Yes	Trafficking, endocytosis
N-CoR	Yes	Nuclear receptor co-repressor
NF-κB	Not known	Transcription factor
p53	No	Transcription factor
PACSIN1	Yes	Endocytosis, actin cytoskeleton
PSD-95	Yes	Postsynaptic Density 95
RasGAP	Not known	Ras GTPase activating protein
SH3GL3	Yes	Endocytosis
SIN3A	Yes	Transcriptional repressor
Sp1	Yes	Transcription factor

Huntingtin has also been shown to interact with:

• HIP2,
• MAP3K10,
• OPTN,
• PRPF40A,
• RASA1,
• SETD2,
• TRIP10,
• ZDHHC17.

Mitochondrial dysfunction

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.

Clinical significance

Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats

Repeat count	Classification	Disease status
<26 span="">	Normal	Unaffected
27–35	Intermediate	Unaffected
36–40	Reduced penetrance	+/- Affected
>40	Full penetrance	Affected

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 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" (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 striatum (a part of the brain that coordinates movement) primarily, and the 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.