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 PDB Ortholog search: PDBe RCSB List of PDB id codes 3IO6, 3IOU, 3LRH, 4FE8, 4FEB, 4FEC, 4FED, 2LD0, 2LD2, 3IO4, 3IOR, 3IOT, 3IOV, 3IOW, 4RAV
Identifiers
Aliases	HTT, HD, IT15, huntingtin, LOMARS
External IDs	OMIM: 613004 MGI: 96067 HomoloGene: 1593 GeneCards: HTT
Gene location (Human) Chr. Chromosome 4 (human)^[1] Band 4p16.3 Start 3,041,363 bp^[1] End 3,243,957 bp^[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)^[2] Band 5 B2|5 17.92 cM Start 34,919,084 bp^[2] End 35,069,878 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sural nerve body of pancreas stromal cell of endometrium Achilles tendon skin of abdomen islet of Langerhans prefrontal cortex gastrocnemius muscle upper lobe of left lung ganglionic eminence Top expressed in entorhinal cortex mammillary body superior colliculus primary motor cortex Paneth cell cerebellar cortex cerebellar vermis superior frontal gyrus ventromedial nucleus inferior colliculus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function profilin binding dynactin binding transmembrane transporter binding p53 binding transcription factor binding protein binding beta-tubulin binding identical protein binding dynein intermediate chain binding kinase binding heat shock protein binding Cellular component late endosome Golgi apparatus nucleoplasm autophagosome endoplasmic reticulum centriole cytoplasmic vesicle membrane dendrite cytosol axon nucleus cytoplasm inclusion body perinuclear region of cytoplasm protein-containing complex presynaptic cytosol postsynaptic cytosol Biological process animal organ development retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum Golgi organization vesicle transport along microtubule negative regulation of extrinsic apoptotic signaling pathway establishment of mitotic spindle orientation positive regulation of cilium assembly positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity apoptotic process vocal learning positive regulation of lipophagy positive regulation of autophagy of mitochondrion positive regulation of aggrephagy regulation of phosphoprotein phosphatase activity protein destabilization positive regulation of apoptotic process regulation of CAMKK-AMPK signaling cascade regulation of cAMP-dependent protein kinase activity Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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

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:

• HIP2,^[26]
• MAP3K10,^[27]
• OPTN,^[28]
• PRPF40A,^[29]
• SETD2,^[29]
• TRIP10,^[30]
• ZDHHC17.^[29][31]

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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Further reading

• Kosinski CM, Schlangen C, Gellerich FN, Gizatullina Z, Deschauer M, Schiefer J, et al. (August 2007). "Myopathy as a first symptom of Huntington's disease in a Marathon runner". Movement Disorders. 22 (11): 1637–40. doi:10.1002/mds.21550. PMID 17534945. S2CID 30904037.
• Bates G (May 2003). "Huntingtin aggregation and toxicity in Huntington's disease". Lancet. 361 (9369): 1642–4. doi:10.1016/S0140-6736(03)13304-1. PMID 12747895. S2CID 7587406.
• Cattaneo E (Feb 2003). "Dysfunction of wild-type huntingtin in Huntington disease". News in Physiological Sciences. 18: 34–7. doi:10.1152/nips.01410.2002. PMID 12531930.
• Gárdián G, Vécsei L (Oct 2004). "Huntington's disease: pathomechanism and therapeutic perspectives". Journal of Neural Transmission. 111 (10–11): 1485–94. doi:10.1007/s00702-004-0201-4. PMID 15480847. S2CID 2961376.
• Landles C, Bates GP (Oct 2004). "Huntingtin and the molecular pathogenesis of Huntington's disease. Fourth in molecular medicine review series". EMBO Reports. 5 (10): 958–63. doi:10.1038/sj.embor.7400250. PMC 1299150. PMID 15459747.
• Jones AL (Jun 1999). "The localization and interactions of huntingtin". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 354 (1386): 1021–7. doi:10.1098/rstb.1999.0454. PMC 1692601. PMID 10434301.
• Li SH, Li XJ (Oct 2004). "Huntingtin and its role in neuronal degeneration". The Neuroscientist. 10 (5): 467–75. doi:10.1177/1073858404266777. PMID 15359012. S2CID 19491573.
• MacDonald ME, Novelletto A, Lin C, Tagle D, Barnes G, Bates G, Taylor S, Allitto B, Altherr M, Myers R (May 1992). "The Huntington's disease candidate region exhibits many different haplotypes". Nature Genetics. 1 (2): 99–103. doi:10.1038/ng0592-99. PMID 1302016. S2CID 25472459.
• MacDonald ME (Nov 2003). "Huntingtin: alive and well and working in middle management". Science's STKE. 2003 (207): pe48. doi:10.1126/stke.2003.207.pe48. PMID 14600292. S2CID 35318234.
• Myers RH (Apr 2004). "Huntington's disease genetics". NeuroRx. 1 (2): 255–62. doi:10.1602/neurorx.1.2.255. PMC 534940. PMID 15717026.
• Rangone H, Humbert S, Saudou F (Jul 2004). "Huntington's disease: how does huntingtin, an anti-apoptotic protein, become toxic?". Pathologie-Biologie. 52 (6): 338–42. doi:10.1016/j.patbio.2003.06.004. PMID 15261377.
• Young AB (Feb 2003). "Huntingtin in health and disease". The Journal of Clinical Investigation. 111 (3): 299–302. doi:10.1172/JCI17742. PMC 151871. PMID 12569151.

External links

• Huntingtin+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• at HOPES : Huntington's Outreach Project for Education at Stanford
• The HDA Huntington's Disease Association UK
• Online Mendelian Inheritance in Man (OMIM): 143100
• EntrezGene 3064