Huntingtin
Encyclopedia
The Huntingtin gene
, also called 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
.
It is variable in its structure, as there are many polymorphisms
of the gene that 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 greater 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 be involved in signalling, 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.
, that is repeated multiple times. This region is called a trinucleotide repeat. Normal persons have a CAG repeat count of between 7 and 35 repeats.
The HD gene is located on the short (p) arm of chromosome 4
at position 16.3, from base pair
3,113,411 to base pair 3,282,655.
) 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 vesicle
s 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 absorption of materials into a cell.
(HAP1) and huntingtin Interacting Protein 1
(HIP1), these were typically found using two-hybrid screening
and confirmed using Immunoprecipitation
.
Huntingtin has also been shown to interact
with:
(HD) is caused by a mutation in the Huntingtin gene, where the CAG repeats more than 36 times and is unstable. 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 or NIIs, inside nerve cells and may attract other, normal proteins into the clumps. It was once thought that the presence of these clumps played a causal role in Huntington disease. Further research undermined this conclusion by showing that the presence of NIIs actually extended the life of neurons and acted to reduce intracelluar 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.
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, also called HTT or HD (Huntington disease) gene, is the IT15 ("interesting transcript 15") gene which codes for a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
called the huntingtin protein. The gene and its product are under heavy investigation as part of Huntington's disease clinical research
Huntington's disease clinical research
There are different therapies under investigation for Huntington's disease. Huntington's disease is a genetic neurological disorder characterized after onset by uncoordinated, jerky body movements and a decline in some mental abilities for which there is no cure or effective treatments...
.
It is variable in its structure, as there are many polymorphisms
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
of the gene that can lead to variable numbers of glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
residues present in the protein. In its wild-type (normal) form, it contains 6-35 glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
residues. However, in individuals affected by Huntington's Disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
(an autosomal dominant genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
), it contains greater 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
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
. 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 be involved in signalling, transporting materials, binding proteins and other structures, and protecting against programmed cell death (apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
). The huntingtin protein is required for normal development before birth
Birth
Birth is the act or process of bearing or bringing forth offspring. The offspring is brought forth from the mother. The time of human birth is defined as the time at which the fetus comes out of the mother's womb into the world...
. 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 3 DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid glutamineGlutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
, that is repeated multiple times. This region is called a trinucleotide repeat. Normal persons have a CAG repeat count of between 7 and 35 repeats.
The HD gene is located on the short (p) arm of chromosome 4
Chromosome 4 (human)
125px|rightChromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 186 million base pairs and represents between 6 and 6.5 percent of the total DNA in cells.Identifying genes on each chromosome is an active area...
at position 16.3, from base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a 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 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 (BDNFBrain-derived neurotrophic factor
Brain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the "neurotrophin" family of growth factors, which are related to the canonical "Nerve Growth Factor", NGF...
) at the transcription level but the mechanism by which huntingtin regulates gene expression has not been determined. From immunohistochemistry
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
, electron microscopy, and subcellular fractionation studies of the molecule, it has been found that huntingtin is primarily associated with vesicle
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
s and microtubules. These appear to indicate a functional role in cytoskeletal anchoring or transport of mitochondria. The Htt protein is involved in vesicle
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
trafficking as it interacts with HIP1, a clathrin
Clathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1975. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice...
binding protein, to mediate endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
, the absorption of materials into a cell.
Interactions
Huntingtin has been found to interact directly with at least 19 other proteins, of which 6 are used for transcription, 4 for transport, 3 for cell signalling, and 6 others of unknown function (HIP5, HIP11, HIP13, HIP15, HIP16, and CGI-125). Over 100 interacting proteins have been found such as huntingtin-associated protein 1Huntingtin-associated protein 1
Huntingtin-associated protein 1 is a protein which in humans is encoded by the HAP1 gene. This protein was found to bind to the mutant huntingtin protein in proportion to the number of glutamines present in the glutamine repeat region....
(HAP1) and huntingtin Interacting Protein 1
Hip-1
Huntingtin Interacting Protein or Hip-1 for short is a protein that interacts with the huntingtin protein. It is known to contain a domain homologous to the death effector domains found on proteins involved in apoptosis...
(HIP1), these were typically found using two-hybrid screening
Two-hybrid screening
Two-hybrid screening is a molecular biology technique used to discover protein–protein interactions and protein–DNA interactions by testing for physical interactions between two proteins or a single protein and a DNA molecule, respectively.The premise behind the test is the activation of...
and confirmed using Immunoprecipitation
Immunoprecipitation
Immunoprecipitation is the technique of precipitating a protein antigen out of solution using an antibody that specifically binds to that particular protein. This process can be used to isolate and concentrate a particular protein from a sample containing many thousands of different proteins...
.
| Interacting Protein | PolyQ length dependence | Function |
|---|---|---|
| α-adaptin C/HYPJ AP2A2 AP-2 complex subunit alpha-2 is a protein that in humans is encoded by the AP2A2 gene.-Interactions:AP2A2 has been shown to interact with EPN1 and SHC1.-Further reading:... |
Yes | Endocytosis |
| Akt AKT1 RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. Multiple alternatively spliced transcript variants have been found for this gene.- Function :... /PKB |
No | Kinase |
| CBP CREB binding protein CREB-binding protein, also known as CREBBP or CBP, is a protein that in humans is encoded by the CREBBP gene.The CREB protein carries out its function by activating transcription, where interaction with transcription factors is managed by one or more of p300 domains: the nuclear receptor... |
Yes | Transcriptional co-activator with acetyltransferase activity |
| CA150 Transcription elongation regulator 1 Transcription elongation regulator 1, also known as TCERG1, is a protein which in humans is encoded by the TCERG1 gene.- Function :This gene encodes a nuclear protein that regulates transcriptional elongation and pre-mRNA splicing... |
No | Transcriptional activator |
| CIP4 TRIP10 Cdc42-interacting protein 4 is a protein that in humans is encoded by the TRIP10 gene.-Interactions:TRIP10 has been shown to interact with STAT3, Wiskott-Aldrich syndrome protein, Huntingtin, CDC42, AKAP9 and RHOQ.-Further reading:... |
Yes | cdc42-dependent signal transduction |
| CtBP RBBP8 Retinoblastoma-binding protein 8 is a protein that in humans is encoded by the RBBP8 gene.-Interactions:RBBP8 has been shown to interact with LMO4, Retinoblastoma-like protein 2, Retinoblastoma-like protein 1, Ataxia telangiectasia mutated, Retinoblastoma protein, CTBP1, SIAH1 and BRCA1.-Further... |
Yes | Transcription factor |
| FIP2 Optineurin Optineurin is a protein that in humans is encoded by the OPTN gene.-Interactions:Optineurin has been shown to interact with Huntingtin and RAB8A.-Further reading:... |
Not known | Cell Morphogenesis |
| Grb2 Grb2 Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene.... |
Not known | Growth factor receptor binding protein |
| HAP1 Huntingtin-associated protein 1 Huntingtin-associated protein 1 is a protein which in humans is encoded by the HAP1 gene. This protein was found to bind to the mutant huntingtin protein in proportion to the number of glutamines present in the glutamine repeat region.... |
Yes | Membrane trafficking |
| HAP40 | Not known | Unknown |
| HIP1 Hip-1 Huntingtin Interacting Protein or Hip-1 for short is a protein that interacts with the huntingtin protein. It is known to contain a domain homologous to the death effector domains found on proteins involved in apoptosis... |
Yes | Endocytosis, proapoptotic |
| HIP14 ZDHHC17 Palmitoyltransferase ZDHHC17 is an enzyme that contains a DHHC domain that in humans is encoded by the ZDHHC17 gene.-Interactions:ZDHHC17 has been shown to interact with Huntingtin.-Further reading:... /HYP-H |
Yes | Trafficking, endocytosis |
| N-CoR Nuclear receptor co-repressor 1 The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 is a protein that in humans is encoded by the NCOR1 gene.... |
Yes | Nuclear receptor co-repressor |
| NF-κB | Not known | Transcription factor |
| p53 P53 p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer... |
No | Transcription factor |
| PACSIN1 PACSIN1 Protein kinase C and casein kinase substrate in neurons protein 1 is an enzyme that in humans is encoded by the PACSIN1 gene.-Interactions:PACSIN1 has been shown to interact with DNM1, PACSIN3, Huntingtin and PACSIN2.-Further reading:... |
Yes | Endocytosis, actin cytoskeleton |
| PSS-95 | Yes | Synaptic scaffolding protein |
| RasGAP | Not known | Ras GTPase activating protein |
| SH3GL3 SH3GL3 Endophilin-A3 is a protein that in humans is encoded by the SH3GL3 gene.-Interactions:SH3GL3 has been shown to interact with Huntingtin and SH3KBP1.-Further reading:... |
Yes | Endocytosis |
| SIN3A SIN3A Paired amphipathic helix protein Sin3a is a protein that in humans is encoded by the SIN3A gene.-Interactions:SIN3A has been shown to interact with HDAC9, OGT, RBBP7, RBBP4, Host cell factor C1, MXD1, IKZF1, Nuclear receptor co-repressor 2, SAP130, KLF11, Methyl-CpG-binding domain protein 2, HDAC1,... |
Yes | Transcriptional repressor |
| Sp1 | Yes | Transcription factor |
Huntingtin has also been shown to interact
Protein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- HIP2HIP2Ubiquitin-conjugating enzyme E2 K is a protein that in humans is encoded by the UBE2K gene.The protein encoded by this gene belongs to the ubiquitin-conjugating enzyme family. It binds selectively to a large region at the N terminus of huntingtin. This interaction is not influenced by the length of...
, - MAP3K10MAP3K10Mitogen-activated protein kinase kinase kinase 10 is an enzyme that in humans is encoded by the MAP3K10 gene.-Interactions:MAP3K10 has been shown to interact with NEUROD1, Huntingtin, MAPK8IP1, KIF3A, CDC42 and MAPK8IP2.-Further reading:...
, - OPTNOptineurinOptineurin is a protein that in humans is encoded by the OPTN gene.-Interactions:Optineurin has been shown to interact with Huntingtin and RAB8A.-Further reading:...
, - PRPF40APRPF40APre-mRNA-processing factor 40 homolog A is a protein that in humans is encoded by the PRPF40A gene.-Interactions:PRPF40A has been shown to interact with Huntingtin.-Further reading:...
, - RASA1RAS p21 protein activator 1RAS p21 protein activator 1 or RasGAP , also known as RASA1, is a 120-kDa cytosolic human protein that provides two principal activities:...
, - SETD2SETD2Histone-lysine N-methyltransferase SETD2 is an enzyme that in humans is encoded by the SETD2 gene.-Interactions:SETD2 has been shown to interact with Huntingtin.-Further reading:...
, - TRIP10TRIP10Cdc42-interacting protein 4 is a protein that in humans is encoded by the TRIP10 gene.-Interactions:TRIP10 has been shown to interact with STAT3, Wiskott-Aldrich syndrome protein, Huntingtin, CDC42, AKAP9 and RHOQ.-Further reading:...
, - ZDHHC17ZDHHC17Palmitoyltransferase ZDHHC17 is an enzyme that contains a DHHC domain that in humans is encoded by the ZDHHC17 gene.-Interactions:ZDHHC17 has been shown to interact with Huntingtin.-Further reading:...
.
Clinical significance
Huntington's diseaseHuntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
(HD) is caused by a mutation in the Huntingtin gene, where the CAG repeats more than 36 times and is unstable. These expanded repeats lead to production of a huntingtin protein that contains an abnormally long polyglutamine tract
Polyglutamine tract
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....
at the N-terminus. This makes it part of a class of neurodegenerative disorders known as trinucleotide repeat disorders
Trinucleotide repeat disorders
Trinucleotide repeat disorders are a set of genetic disorders caused by trinucleotide repeat expansion, a kind of mutation where trinucleotide repeats in certain genes exceeding the normal, stable, threshold, which differs per gene...
or polyglutamine disorders. The key sequence which is found in Huntington's disease is a trinucleotide repeat expansion
Trinucleotide repeat disorders
Trinucleotide repeat disorders are a set of genetic disorders caused by trinucleotide repeat expansion, a kind of mutation where trinucleotide repeats in certain genes exceeding the normal, stable, threshold, which differs per gene...
of glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
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 or NIIs, inside nerve cells and may attract other, normal proteins into the clumps. It was once thought that the presence of these clumps played a causal role in Huntington disease. Further research undermined this conclusion by showing that the presence of NIIs actually extended the life of neurons and acted to reduce intracelluar 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
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
(a part of the brain that coordinates movement) primarily, and the frontal cortex (a part of the brain that controls thinking and emotions).
| Repeat count | Classification | Disease status |
|---|---|---|
| <28 | Normal | Unaffected |
| 28–35 | Intermediate | Unaffected |
| 36–40 | Reduced Penetrance | +/- Affected |
| >40 | Full Penetrance | Affected |
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.
External links
- The Huntingtin Protein and Protein Aggregation at HOPES : Huntington's Outreach Project for Education at Stanford
- The HDA Huntington's Disease Association UK
- GeneCard
- iHOP