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Huntingtin (Htt) is the
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
coded for in humans by the ''HTT''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
, also known as the ''IT15'' ("interesting transcript 15") gene.
Mutated In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitos ...
''HTT'' is the cause of
Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...
(HD), and has been investigated for this role and also for its involvement 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 Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
residues present in the protein. In its
wild-type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
(normal form), it contains 6-35 glutamine residues. However, in individuals affected by Huntington's disease (an
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
), 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 The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
. 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 cell A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. No ...
s. Within cells, huntingtin may or may not be involved in signaling, transporting materials, binding proteins and other structures, and protecting against
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, a form of
programmed cell death Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell (biology), cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers ...
. The huntingtin protein is required for normal development before
birth Birth is the act or process of bearing or bringing forth offspring, also referred to in technical contexts as parturition. In mammals, the process is initiated by hormones which cause the muscular walls of the uterus to contract, expelling the f ...
. 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 Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
, 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 Chromosome 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 (the building material of DNA) and represents between 6 and 6.5 percent of the t ...
at position 16.3, from base pair 3,074,510 to base pair 3,243,960.


Protein


Function

The function of huntingtin (Htt) is not well understood but it is involved in
axonal transport Axonal transport, also called axoplasmic transport or axoplasmic flow, is a cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, through the cytopla ...
. Huntingtin is essential for development, and its absence is lethal in mice. The protein has no
sequence homology Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spe ...
with other proteins and is highly expressed in neurons and testes in humans and rodents. Huntingtin upregulates the expression of
brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. 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 canon ...
(BDNF) at the transcription level, but the mechanism by which huntingtin regulates gene expression has not been determined. From
immunohistochemistry Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to an ...
, electron microscopy, and subcellular fractionation studies of the molecule, it has been found that huntingtin is primarily associated with
vesicle Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry) In cell biology, a vesicle is a structure within or outside a cell, consisting of liquid or cytoplasm enclosed by a lipid bilayer. Vesicles form nat ...
s and
microtubules Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27  nm and have an inner diameter between 11 a ...
. 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 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 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When ...
-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 Ras-related protein Rab-11A is a protein that in humans is encoded by the ''RAB11A'' gene. Function The protein encoded by this gene belongs to the small GTPase superfamily, Rab family. It is associated with both constitutive and regulated secr ...
.


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 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 () in proportion to the number of glutamines present in the glutamine repeat regio ...
(HAP1) and huntingtin interacting protein 1 (HIP1), these were typically found using
two-hybrid screening Two-hybrid screening (originally known as yeast two-hybrid system or Y2H) is a molecular biology technique used to discover protein–protein interactions (PPIs) and protein–DNA interactions by testing for physical interactions (such as bindi ...
and confirmed using immunoprecipitation. Huntingtin has also been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with: *
HIP2 Ubiquitin-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 hunti ...
, *
MAP3K10 Mitogen-activated protein kinase kinase kinase 10 is an enzyme that in humans is encoded by the ''MAP3K10'' gene. Function The protein encoded by this gene is a member of the serine/threonine kinase family. This kinase has been shown to activa ...
, * OPTN, * PRPF40A, *
SETD2 SET domain containing 2 is an enzyme that in humans is encoded by the ''SETD2'' gene. Function SETD2 protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active c ...
, *
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 Rho-related GTP-bindi ...
, * ZDHHC17.


Mitochondrial dysfunction

Huntingtin is a
scaffolding protein In biology, scaffold proteins are crucial regulators of many key signalling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signalling pathway, tethering them in ...
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 In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...
and increased
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
. The promotion of oxidative damage to DNA may contribute to
Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...
pathology.


Clinical significance

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 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. A multitude of genes, in various eukaryotic species (including h ...
at the N-terminus. This makes it part of a class of neurodegenerative disorders known as
trinucleotide repeat disorders 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 ( trinucleotide repeats) inc ...
or polyglutamine disorders. The key sequence which is found in Huntington's disease is a trinucleotide repeat expansion of
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
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 mutant form of Htt, (mHtt). Reduced
penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...
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 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 (clumps) 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: (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. This process is particularly likely to occur in the
striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...
(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.


References


Further reading

* * * * * * * * * * * *


External links

*
The Huntingtin Protein and Protein Aggregation
a
HOPES
: Huntington's Outreach Project for Education at Stanford
The HDA
Huntington's Disease Association UK * * {{EntrezGene, 3064
GeneCard


Human proteins Huntington's disease Genes on human chromosome 4