HTT
Huntingtin is a disease gene linked to Huntington's disease, a neurodegenerative disorder characterized by loss of striatal neurons. This is thought to be caused by an expanded, unstable trinucleotide repeat in the huntingtin gene, which translates as a polyglutamine repeat in the protein product. A fairly broad range of trinucleotide repeats (9-35) has been identified in normal controls, and repeat numbers in excess of 40 have been described as pathological. The huntingtin locus is large, spanning 180 kb and consisting of 67 exons. The huntingtin gene is widely expressed and is required for normal development. It is expressed as 2 alternatively polyadenylated forms displaying different relative abundance in various fetal and adult tissues. The larger transcript is approximately 13.7 kb and is expressed predominantly in adult and fetal brain whereas the smaller transcript of approximately 10.3 kb is more widely expressed. The genetic defect leading to Huntington's disease may not necessarily eliminate transcription, but may confer a new property on the mRNA or alter the function of the protein. One candidate is the huntingtin-associated protein-1, highly expressed in brain, which has increased affinity for huntingtin protein with expanded polyglutamine repeats. This gene contains an upstream open reading frame in the 5' UTR that inhibits expression of the huntingtin gene product through translational repression. [provided by RefSeq, Jul 2016]
Function
Huntingtin:
May play a role in microtubule-mediated transport or vesicle function.
Huntingtin, myristoylated N-terminal fragment:
Promotes the formation of autophagic vesicles.
Biological Process
Apoptotic process Source: UniProtKB-KW
Establishment of mitotic spindle orientation Source: UniProtKB
Golgi organization Source: UniProtKB
Microtubule-based transport Source: GO_Central
Negative regulation of extrinsic apoptotic signaling pathway Source: UniProtKB
Positive regulation of aggrephagy Source: ParkinsonsUK-UCL
Positive regulation of apoptotic process Source: CAFA
Positive regulation of autophagy of mitochondrion Source: ParkinsonsUK-UCL
Positive regulation of cilium assembly Source: SYSCILIA_CCNET
Positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity Source: UniProtKB
Positive regulation of lipophagy Source: ParkinsonsUK-UCL
Protein destabilization Source: CAFA
Regulation of CAMKK-AMPK signaling cascade Source: ARUK-UCL
Regulation of cAMP-dependent protein kinase activity Source: ARUK-UCL
Regulation of phosphoprotein phosphatase activity Source: dictyBase
Retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum Source: UniProtKB
Vesicle transport along microtubule Source: UniProtKB
Vocal learning Source: AgBase
Cellular Location
Huntingtin: Nucleus; Early endosome; Cytoplasm. The mutant Huntingtin protein colocalizes with AKAP8L in the nuclear matrix of Huntington disease neurons. Shuttles between cytoplasm and nucleus in a Ran GTPase-independent manner (PubMed:15654337). Recruits onto early endosomes in a Rab5- and HAP40-dependent fashion (PubMed:16476778).
Huntingtin, myristoylated N-terminal fragment: Autophagosome
Involvement in disease
Huntington disease (HD):
A neurodegenerative disorder characterized by involuntary movements (chorea), general motor impairment, psychiatric disorders and dementia. Onset of the disease occurs usually in the third or fourth decade of life. Onset and clinical course depend on the degree of poly-Gln repeat expansion, longer expansions resulting in earlier onset and more severe clinical manifestations. Neuropathology of Huntington disease displays a distinctive pattern with loss of neurons, especially in the caudate and putamen.
Lopes-Maciel-Rodan syndrome (LOMARS):
An autosomal recessive neurodevelopmental disorder characterized by developmental regression in infancy, delayed psychomotor development, severe intellectual disability, and cerebral and cerebellar atrophy. Additional features include swallowing problems, dystonia, bradykinesia, and continuous manual stereotypies without chorea. Some patients manifest seizures.
PTM
Huntingtin:
Cleaved by caspases downstream of the polyglutamine stretch (PubMed:8696339, PubMed:9535906, PubMed:10770929, PubMed:29802276). The resulting N-terminal fragments are cytotoxic and provokes apoptosis (PubMed:10770929).
Huntingtin:
Forms with expanded polyglutamine expansion are specifically ubiquitinated by SYVN1, which promotes their proteasomal degradation.
Huntingtin:
Phosphorylation at Ser-1179 and Ser-1199 by CDK5 in response to DNA damage in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity.
Huntingtin, myristoylated N-terminal fragment:
Myristoylated at Gly-551, following proteolytic cleavage at Asp-550.
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Datasheet