Selected-GenAtlas references	SOURCE	GeneCards	NCBI Gene	Swiss-Prot	Orphanet	Ensembl
	HGNC	UniGene	Nucleotide	OMIM		UCSC

Home Page

FLASH GENE

Symbol

HTT

contributors: mct/pgu/shn - updated : 03-06-2019

HGNC name	huntingtin
HGNC id	4851

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_002111 67 polyA site 13481 NP_002102 347.7 3144 adult and fetal brain 2007 2889660 variant HDT1

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Endocrine parathyroid       highly Lymphoid/Immune lymph node       highly Nervous brain forebrain cerebral cortex       brain basal nuclei striatum       brain diencephalon hypothalamus     Reproductive female system ovary       Respiratory lung       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine   Nervous central

cell lineage	required for the generation and expression of hematopoietic cells
cell lines
fluid/secretion

at STAGE

physiological period

fetal

Text	brain, eye

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal 17 AAs domain, sequence highly conserved across species, having properties of a cytosolic retention signal, required for mitochondrial association, playing a key role in regulating its toxicity and aggregation, and acting as a nuclear export sequence (NES) within HTT exon , associated to a KPNB2-dependent proline-tyrosine (PY)-NLS
	a stretch of glutamine encoded by CCG repeat and CAG repeat
	ten HEAT repeats
	five pentapeptide motif (LxxLL) not necessary for the huntingtin-NR1H3 interaction or for activation of NR1H3 mediated transcription
	the first 17 AAs, the proline-rich sequence C-terminal with an expanded polyQ peptide decreases aggregate, influencing sub-cellular localization, protein stability, binding to the SH3 domain of DLG4 (

secondary structure

a large hinged {alpha}-helical solenoid, which serves as a facilitator of the PRC2 complex, now provides a nuanced view of the molecule and its polymorphic polyglutamine region

HOMOLOGY

interspecies	ortholog to Htt, Mus musculus
	ortholog to Htt, Rattus norvegicus
	ortholog to htt, danio rerio
	ortholog to HTT, Pan troglodyts

Homologene

FAMILY

hungtintin family

CATEGORY

transport

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,organelle,endosome
	intracellular,cytoplasm,organelle,lysosome
	intracellular,cytoplasm,cytosolic,vesicle
	intracellular,cytoplasm,cytoskeleton,microtubule
	intracellular,nucleus,nucleoplasm,nuclear bodies,nuclear speckles
	intracellular,nucleus,nucleolus
text	distinct subsets of cytoplasmic and nuclear organelles
	N-terminus shuttles between the cytoplasm and nucleus in an Ran-GTPase- independent manner
	clathrin-coated and non-coated vesicles
	perinuclear subcellular localization with a potential role in trafficking a discrete set of proteins between the Golgi and the extracellular space
	in the HD brain, localized mainly in the cytoplasm; however, a small portion of mutant HTT localizes in subcellular organelles, including the plasma membrane, mitochondria, lysosomes and endoplasmic reticulum
	found both in the nucleus and in the cytoplasm where it associates with a variety of organelles, including endoplasmic reticulum, Golgi apparatus, and mitochondria
	primarily a cytoplasmic protein, known to be both vesicle- and microtubule-associated
	association of HTT to the ER membrane is mediated by the first 18 amino acids, and this association is affected by ER stress (

basic FUNCTION	involved in intracellular organelle or axonal transport and in the organization of the centrosome
	interacting with CREBBP and TP53 for transcription repression
	iron Fe2+ regulated protein essential for normal nuclear and perinuclear organelles
	involved in RNA biogenesis and cellular trafficking by control of UPP (ubiquitin proteasome pathway)
	stimulating endosomal-lysosomal activity and autophagic process of cell death
	playing a role in the regulation of microtubule-mediated transport or vesicle function (particularly BDNF transport)
	acting in the cytoplasm of neurons to regulate the availability of REST to its nuclear NRSE-binding site
	playing an integral role in mitochondrial energy metabolism (polyglutamine tract appears to regulate mitochondrial ADP-phosphorylation in a Ca(2+)-dependent process )
	playing a role in MAPK pathway, in the ERK and JNK activation
	playing a role in the intracellular trafficking of proteins required for the construction of the extracellular matrix
	involved in NF-Y sequesteration leading to the reduction of HSPA4 gene expression
	may be a component of a P body and functions in post-transcriptional repression pathways
	being a positive regulatory factor for vesicular transport (promoting anterograde transport, when phosphorylated)
	required for the generation and expansion of hematopoietic cells (
	implicated in numerous cellular processes such as transcriptional regulation, mitochondria energetics, structural scaffolding, vesicle trafficking, endocytosis, and dentrite formation
	positive regulatory factor for vesicular transport whose function is lost in disease
	role in the regulation of cerebral spinal fluid (CSF) homeostasis (
	exerts anti-apoptotic effects by binding to PAK2, which reduces the abilities of caspase-3 and caspase-8 to cleave PAK2 and convert it into a mediator of cell death
	regulates the assembly of the dynein–dynactin complex for axonal transport and Golgi apparatus organization
	may regulate expression of ABCG1 and CYP7A1 via multiple targets
	with HAP1, participate in intracellular trafficking and polyglutamine expansion affects vesicular transport
	may function to repress translation of mRNA during transport in neuronal granules
	stimulates the transport of nuclear factor kappa light-chain-enhancer of activated B cells (NF-KB) out of dendritic spines (where NF-KB is activated by excitatory synaptic input) (
	may play potentially a role similar to that of importin-beta1 in the retrograde transport of nuclear localization signal-containing cargoes from synapses toward the nucleus (
	could participate in the distribution of the dynein–dynactin complex at the cell cortex and, as a consequence, regulate mitosis at several points
	regulates cortical neurogenesis through, at least in part, its role during spindle pole orientation
	role in the dynein-mediated intracellular trafficking of endosomes and lysosomes (
	important biochemical function for HTT modulation of ZDHHC17 palmitoylation and its enzymatic activity
	in addition to serving as a palmitoylation substrate, wild-type HTT also modulates the palmitoylation of ZDHHC17 itself
	is required for multiple stages of neural induction, whereas mutant HTT enhances this process and promotes precocious neurogenesis and oligodendrocyte progenitor cell elaboration
	HTT and HAP1 are regulators of autophagosome transport in neurons, suggesting that misregulation of autophagosome transport in Huntington disease leads to inefficient autophagosome maturation, potentially due to inhibition of autophagosome/lysosome fusion along the axon
	is involved directly in membrane dynamics, cell attachment, and motility
	is necessary for mitochondrial structure and function from the earliest stages of embryogenesis
	is a component of the pathway regulating the orientation of mammary stem cell division, with potential implications for their self-renewal and differentiation properties
	cortical HTT is required for the correct establishment of cortical and striatal excitatory circuits, and this function of HTT is lost when the mutant HTT is present
	functions as a scaffold protein for selective macroautophagy but it is dispensable for non-selective macroautophagy
	important for ciliogenesis and potentially implicated in autosomal dominant polycystic kidney disease (ADPKD)

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

cellular trafficking transport

PATHWAY

metabolism

signaling

a component

REST, DCTN1, HTT, HAP1, and RILP form a complex involved in the translocation of REST into the nucleus and HAP1 controls REST cellular localization in neurons

INTERACTION

DNA

RNA

small molecule

microtubule motors AND actin-associated adaptor molecules

protein	microtubular calmodulin, EGFR, CBS, and TGM2
	GAPDH, HAP1, HIP1 and HIP2
	TPR
	SP1 and TAF4
	components of the NF-Y transcriptional factor (NFYA) (mutant form)
	EIF2C2 (localization to P bodies provides evidence connecting HTT with the post-transcriptional control of gene expression and P body integrity)
	human ubiquitin-conjugating enzyme, hE2-25K (
	Grb2, RasGAP, and tyrosine-phosphorylated EGF receptoR (
	cystathionine beta-synthase, CBS (
	huntingtin-associated protein, HAP1 (
	HYPA, HYPB, HYPC spliceosome proteins (
	SH3-domain GRB2-like 3, SH3GL3 (
	nuclear receptor co-repressor, N-CoR (
	mixed-lineage kinase 2, MLK2 (
	p53 and CREB-binding protein (
	40-kDa Huntingtin-associated protein, HAP40 (
	Huntingtin-interacting protein I, HIP1 (
	carboxy-terminal region of FIP-2 (
	associated with N-methyl-d-aspartate (NMDA) and kainate receptors via postsynaptic density 95 (
	transcriptional corepressor C-terminal binding protein, CtBP (
	transcriptional activator Sp1 (
	beta-tubulin (
	serine/threonine protein kinase Akt (
	protein kinase C and casein kinase substrate in neurons 1, PACSIN1 (
	Huntingtin-interacting protein 14, HIP14 (
	Cdc42-interacting protein 4, CIP4 (
	repressor element-1 transcription factor, REST/neuron restrictive silencer element, NRSE (
	caspase-2, CASP2 (
	toxic huntingtin interacts with the benign polyQ repeat of TATA box binding protein (
	Mutant huntingtin bound much stronger to CREB binding protein (
	link between RAB5A, F8A1, and HTT, suggesting mechanism regulating cytoskeleton-dependent endosome dynamics and its dysfunction under pathological conditions
	PFN1 interacts with HTT, as being a direct target of the ROCK1 isoform
	Argonaute, AGO2 (
	co-factor of NR1H3 (activity is lost by mutant huntingtin that only interacts weakly with NR1H3)
	nuclear factor kappa light-chain-enhancer of activated B cells NF-KB that has been recently implicated in neural-specific functions
	cytosplasmic dynein, a motor protein that drives cargoes along microtubular tracks toward the minus end
	regulates spindle orientation by ensuring the proper localization of the DCTN1 subunit of dynactin, dynein and NUMA1
	TRAF6 interacts with and ubiquitinates WT and mutant HTT
	may also function as an allosteric activator of ZDHHC17
	HTT regulates ciliogenesis by interacting through HAP1 with pericentriolar material 1 protein (PCM1)
	CALB2 is preferentially associated with mutant HTT, although it also interacts with wild-type HTT
	SRSF6 splicing factor binds to the 5prime end of the HTT gene with an expanded CAG repeat, consistent with its known recognition motif
	may be a co-factor with mutant huntingtin in cell death
	HTT-MECP2 interactions are enhanced in the presence of the expanded polyglutamine (polyQ) tract and are stronger in the nucleus compared with the cytoplasm
	serine/threonine kinase AKT1, which regulates HTT function, rescued the spindle misorientation caused by the mutant HTT, by serine 421 (S421) phosphorylation

cell & other

REGULATION

activated by

upregulation of transcription of brain derived neurotrophic factor (necessary for survival of striatal neurons)

Other	phosphorylated on S421 by the kinase Akt (protective effect against the toxicity of polyglutamine-expansion showing a regional distribution with the highest levels in the cerebellum, less in the cortex, and least in the striatum) (being crucial to control the direction of vesicles in neurons)
	can be cleaved by caspases and calpains at multiple sites within the region between AAs 460 and 600 (14, 19-29); cleavage at position 586 by caspase 6 is of particular importance for HD pathogenesis
	HTT is palmitoylated by ZDHHC17 and 13

ASSOCIATED DISORDERS

corresponding disease(s)

HD

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional       gain of function a toxic gain of function of the mutant huntingtin

Susceptibility

Variant & Polymorphism

Candidate gene	calcium and mitochondrial permeability transition pore blockers may have a therapeutic potential for treatment of HD
Marker
Therapy target

ANIMAL & CELL MODELS

	Homozygotes mice for disruption of exon 5 of the Htt gene (Hdhex5) die before embryonic day 8.5, initiate gastrulation, but do not proceed to the formation of somites or to organogenesis. Mice heterozygous for the Hdhex5 mutation display increased motor activity and cognitive deficits with significant neuronal loss in the subthalamic nucleus
	adult mice with a precise deletion of the short CAG triplet repeat encoding 7Q in the mouse HD gene commit more errors initially in the Barnes circular maze learning and memory test (
	conditional inactivation of the Hdh mouse gene in Wnt1 cell lineages results in congenital hydrocephalus (
	huntingtin loss-of-function on the developing nervous system of zebrafish causes distinct defects in morphology of neuromasts, olfactory placode and branchial arches (
	mice expressing mutant htt, resistant to cleavage by caspase-6 but not caspase-3, maintain normal neuronal function and do not develop striatal neurodegeneration
	Meclizine is neuroprotective in models of Huntington's disease