Huntingtin

Huntingtin (Htt) is the protein coded for in humans by the HTT gene, also known as the IT15 ("interesting transcript 15") gene.[5] Mutated HTT is the cause of Huntington's disease (HD), and has been investigated for this role and also for its involvement in long-term memory storage.[6]

HTT
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesHTT, HD, IT15, huntingtin, LOMARS
External IDsOMIM: 613004 MGI: 96067 HomoloGene: 1593 GeneCards: HTT
Orthologs
SpeciesHumanMouse
Entrez

3064

15194

Ensembl

ENSG00000197386

ENSMUSG00000029104

UniProt

P42858

P42859

RefSeq (mRNA)

NM_002111
NM_001388492

NM_010414

RefSeq (protein)

NP_002102

NP_034544

Location (UCSC)Chr 4: 3.04 – 3.24 MbChr 5: 34.92 – 35.07 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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, the polymorphic locus contains 6-35 glutamine residues. However, in individuals affected by Huntington's disease (an autosomal dominant genetic disorder), the polymorphic locus contains more than 36 glutamine residues (highest reported repeat length is about 250).[7] 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 apoptosis, a form of programmed cell death. The huntingtin protein is required for normal development before birth.[8] It is expressed in many tissues in the body, with the highest levels of expression seen in the brain.

Gene

The 5'-end (five prime end) of the HTT 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. The usual CAG repeat count is between seven and 35 repeats.

The HTT gene is located on the short arm (p) of chromosome 4 at position 16.3, from base pair 3,074,510 to base pair 3,243,960.[9]

Protein

Function

The function of huntingtin (Htt) is not well understood but it is involved in axonal transport.[10] Huntingtin is essential for development, and its absence is lethal in mice.[8] The protein has no sequence homology with other proteins and is highly expressed in neurons and testes in humans and rodents.[11] 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.[12] From immunohistochemistry, electron microscopy, and subcellular fractionation studies of the molecule, it has been found that huntingtin is primarily associated with vesicles and microtubules.[13][14] 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.[15][16] Huntingtin has also been shown to have a role in the establishment in epithelial polarity through its interaction with RAB11A.[17]

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).[18] 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.[19][20]

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[21] Not known Growth factor receptor binding protein
HAP1 Yes Membrane trafficking
HAP40 (F8A1, F8A2, F8A3) 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[22] No Transcription factor
PACSIN1[23] Yes Endocytosis, actin cytoskeleton
DLG4 (PSD-95) Yes Postsynaptic Density 95
RASA1 (RasGAP)[21] Not known Ras GTPase activating protein
SH3GL3[24] Yes Endocytosis
SIN3A Yes Transcriptional repressor
Sp1[25] Yes Transcription factor

Huntingtin has also been shown to interact with:

Mitochondrial dysfunction

Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex. Mutant huntingtin (mHtt) plays a key role in mitochondrial dysfunction involving the inhibition of mitochondrial electron transport, higher levels of reactive oxygen species and increased oxidative stress.[32][33] The promotion of oxidative damage to DNA may contribute to Huntington's disease pathology.[34]

Clinical significance
Main article: Huntington's disease
Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats[35]
Repeat count Classification Disease status
<26 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.[35] 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.[5] However, 36 or more residues produce an erroneous mutant form of Htt, (mHtt). Reduced penetrance is found in counts 36–39.[36]

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 characteristic presence of these clumps in patients was thought to contribute to the development of Huntington disease.[37] However, later research raised questions about the role of the inclusions (clumps) by showing the presence of visible NIIs extended the life of neurons and acted to reduce intracellular mutant huntingtin in neighboring neurons.[38] 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.[39] The likelihood of neuronal death remains difficult to predict. Likely multiple factors are important, including: (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 be helpful as a coping mechanism—and not simply a pathogenic mechanism—to stem neuronal death by decreasing the amount of diffuse huntingtin.[40] 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.[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.

References
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