Huntingtin

Last updated
HTT
PDB 3io4 EBI.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases HTT , HD, IT15, huntingtin, LOMARS
External IDs OMIM: 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 Mb Chr 5: 34.92 – 35.07 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

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 ProteinPolyQ length dependenceFunction
α-adaptin C/HYPJ YesEndocytosis
Akt/PKBNoKinase
CBP YesTranscriptional co-activator with acetyltransferase activity
CA150 NoTranscriptional activator
CIP4 Yescdc42-dependent signal transduction
CtBP YesTranscription factor
FIP2 Not knownCell morphogenesis
Grb2 [21] Not knownGrowth factor receptor binding protein
HAP1 YesMembrane trafficking
HAP40 ( F8A1 , F8A2, F8A3)Not knownUnknown
HIP1 YesEndocytosis, proapoptotic
HIP14/HYP-HYesTrafficking, endocytosis
N-CoR YesNuclear receptor co-repressor
NF-κB Not knownTranscription factor
p53 [22] NoTranscription factor
PACSIN1 [23] YesEndocytosis, actin cytoskeleton
DLG4 (PSD-95)YesPostsynaptic Density 95
RASA1 (RasGAP) [21] Not knownRas GTPase activating protein
SH3GL3 [24] YesEndocytosis
SIN3A YesTranscriptional repressor
Sp1 [25] YesTranscription 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

Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats [35]
Repeat countClassificationDisease status
<26NormalUnaffected
27–35IntermediateUnaffected
36–40Reduced penetrance+/- Affected
>40Full penetranceAffected

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.

Related Research Articles

<span class="mw-page-title-main">Huntington's disease</span> Inherited neurodegenerative disorder

Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental/psychiatric abilities. A general lack of coordination and an unsteady gait often follow. It is also a basal ganglia disease causing a hyperkinetic movement disorder known as chorea. As the disease advances, uncoordinated, involuntary body movements of chorea become more apparent. Physical abilities gradually worsen until coordinated movement becomes difficult and the person is unable to talk. Mental abilities generally decline into dementia, depression, apathy, and impulsivity at times. The specific symptoms vary somewhat between people. Symptoms usually begin between 30 and 50 years of age, and can start at any age but are usually seen around the age of 40. The disease may develop earlier in each successive generation. About eight percent of cases start before the age of 20 years, and are known as juvenile HD, which typically present with the slow movement symptoms of Parkinson's disease rather than those of chorea.

Repeated sequences are short or long patterns of nucleic acids that occur in multiple copies throughout the genome. In many organisms, a significant fraction of the genomic DNA is repetitive, with over two-thirds of the sequence consisting of repetitive elements in humans. Some of these repeated sequences are necessary for maintaining important genome structures such as telomeres or centromeres.

In genetics, anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase in the severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders, such as Huntington's disease and myotonic dystrophy, where a dynamic mutation in DNA occurs. All of these diseases have neurological symptoms. Prior to the understanding of the genetic mechanism for anticipation, it was debated whether anticipation was a true biological phenomenon or whether the earlier age of diagnosis was related to heightened awareness of disease symptoms within a family.

Trinucleotide repeat disorders, also known as microsatellite expansion diseases, are a set of over 50 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides increase in copy numbers until they cross a threshold above which they become unstable. Depending on its location, the unstable trinucleotide repeat may cause defects in a protein encoded by a gene; change the regulation of gene expression; produce a toxic RNA, or lead to chromosome instability. In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes.

<span class="mw-page-title-main">Huntingtin-interacting protein 1</span> Protein-coding gene in the species Homo sapiens

Huntingtin-interacting protein 1 also known as HIP-1 is a protein that in humans is encoded by the HIP1 gene.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system disease

A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

A trinucleotide repeat expansion, also known as a triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations. Triplet expansion is caused by slippage during DNA replication, also known as "copy choice" DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and daughter strand being synthesized. If the loop out structure is formed from the sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally, the larger the expansion the more likely they are to cause disease or increase the severity of disease. Other proposed mechanisms for expansion and reduction involve the interaction of RNA and DNA molecules.

<span class="mw-page-title-main">Ataxin 1</span> Protein-coding gene in the species Homo sapiens

Ataxin-1 is a DNA-binding protein which in humans is encoded by the ATXN1 gene.

<span class="mw-page-title-main">Spinocerebellar ataxia type 6</span> Medical condition

Spinocerebellar ataxia type 6 (SCA6) is a rare, late-onset, autosomal dominant disorder, which, like other types of SCA, is characterized by dysarthria, oculomotor disorders, peripheral neuropathy, and ataxia of the gait, stance, and limbs due to cerebellar dysfunction. Unlike other types, SCA 6 is not fatal. This cerebellar function is permanent and progressive, differentiating it from episodic ataxia type 2 (EA2) where said dysfunction is episodic. In some SCA6 families, some members show these classic signs of SCA6 while others show signs more similar to EA2, suggesting that there is some phenotypic overlap between the two disorders. SCA6 is caused by mutations in CACNA1A, a gene encoding a calcium channel α subunit. These mutations tend to be trinucleotide repeats of CAG, leading to the production of mutant proteins containing stretches of 20 or more consecutive glutamine residues; these proteins have an increased tendency to form intracellular agglomerations. Unlike many other polyglutamine expansion disorders expansion length is not a determining factor for the age that symptoms present.

<span class="mw-page-title-main">Atrophin 1</span> Protein-coding gene in the species Homo sapiens

Atrophin-1 is a protein that in humans is encoded by the ATN1 gene. The encoded protein includes a serine repeat and a region of alternating acidic and basic amino acids, as well as the variable glutamine repeat. The function of Atrophin-1 has not yet been determined. There is evidence provided by studies of Atrophin-1 in animals to suggest it acts as a transcriptional co-repressor. Atrophin-1 can be found in the nuclear and cytoplasmic compartments of neurons. It is expressed in nervous tissue.

Huntingtin-associated protein 1 (HAP1) is a protein which in humans is encoded by the HAP1 gene. This protein was found to bind to the mutant huntingtin protein (mHtt) in proportion to the number of glutamines present in the glutamine repeat region.

<span class="mw-page-title-main">Ataxin 3</span> Protein-coding gene in the species Homo sapiens

Ataxin-3 is a protein that in humans is encoded by the ATXN3 gene.

<span class="mw-page-title-main">PQBP1</span> Protein-coding gene in the species Homo sapiens

Polyglutamine-binding protein 1 (PQBP1) is a protein that in humans is encoded by the PQBP1 gene.

<span class="mw-page-title-main">JPH3</span> Protein-coding gene in the species Homo sapiens

Junctophilin-3 is a protein in humans that is encoded by the JPH3 gene. The gene is approximately 97 kilobases long and is located at position 16q24.2. Junctophilin proteins are associated with the formation of junctional membrane complexes, linking the plasma membrane with the endoplasmic reticulum in excitable cells. Junctophilin-3 is specific to the brain and has an active role in neurons involved in motor coordination and memory.

Ataxin 8 opposite strand, also known as ATXN8OS, is a human gene.

<span class="mw-page-title-main">Dentatorubral–pallidoluysian atrophy</span> Congenital disorder of nervous system

Dentatorubral–pallidoluysian atrophy (DRPLA) is an autosomal dominant spinocerebellar degeneration caused by an expansion of a CAG repeat encoding a polyglutamine tract in the atrophin-1 protein. It is also known as Haw River Syndrome and Naito–Oyanagi disease. Although this condition was perhaps first described by Smith et al. in 1958, and several sporadic cases have been reported from Western countries, this disorder seems to be very rare except in Japan.

A polyglutamine tract or polyQ tract is a portion of a protein consisting of a sequence of several glutamine units. A tract typically consists of about 10 to a few hundred such units.

Pridopidine is an orally administrated small molecule investigational drug. Pridopidine is a selective and potent Sigma-1 Receptor agonist. It is being developed by Prilenia Therapeutics and is currently in late-stage clinical development for Huntington’s disease (HD) and Amyotrophic Lateral Sclerosis (ALS).

<span class="mw-page-title-main">Sarah Tabrizi</span> British neurologist and neuroscientist

Sarah Joanna Tabrizi FMedSci is a British neurologist and neuroscientist in the field of neurodegeneration, particularly Huntington's disease. She is a Professor and Joint Head of the Department of Neurodegenerative Diseases at the UCL Institute of Neurology; the founder and Director of the UCL Huntington's Disease Centre; a Principal Investigator at the UK Dementia Research Institute at UCL; and an Honorary Consultant Neurologist at the National Hospital for Neurology and Neurosurgery, Queen Square, London, where she established the Multidisciplinary Huntington's Disease Clinic. The UCL Huntington’s Disease Centre was officially opened on 1 March 2017 by UCL President and Provost Professor Michael Arthur.

Michelle Gray is an American neuroscientist and assistant professor of neurology and neurobiology at the University of Alabama Birmingham. Gray is a researcher in the study of the biological basis of Huntington's disease (HD). In her postdoctoral work, she developed a transgenic mouse line, BACHD, that is now used worldwide in the study of HD. Gray's research now focuses on the role of glial cells in HD. In 2020 Gray was named one of the 100 Inspiring Black Scientists in America by Cell Press. She is also a member of the Hereditary Disease Foundation’s scientific board.

References

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