Gena/Proteina

1. Caracteristica genei
Locus
Structura (particularitati)
Expresie(Particularitati, splicing)
Reglarea expresiei (TAFs)
2. Caracteristica proteina
Structura/domenii
Localizare in celula
Locul sintezei
Locul/particularitati de maturizare
Functii
Interactiuni
3. Rol medical
4. Bibliografie

Gena Huntingtin HTT

1. Caracteristica genei
Huntingtin is found in many of the body's tissues, with the
highest levels of activity in the brain. Within cells, this
protein may be involved in chemical signaling, transporting
materials, attaching (binding) to proteins and other
structures, and protecting the cell from self-destruction
(apoptosis).
The HD locus spans 180 kb and consists of 67 exons
ranging in size from 48 bp to 341 bp with an average of 138
bp.
Huntingtin is expressed ubiquitously in humans and rodents,
with highest levels in the neurons of the CNS (147, 181, 196,
583, 607). Particularly, huntingtin is enriched in cortical
pyramidal neurons in layers III and V that project to the
striatal neurons (196).
One region of the HTT gene contains a particular DNA
segment known as a CAG trinucleotide repeat. This segment
is made up of a series of three DNA building blocks
(cytosine, adenine, and guanine) that appear multiple times
in a row. Normally, the CAG segment is repeated 10 to 35
times within the gene.
2. Proteina
Within the cell, mammalian huntingtin is associated with a
variety of organelles, including the nucleus, endoplasmic
reticulum, Golgi complex, and mitochondrion (257, 263,
301, 427, 554). It is also found within neurites and at
synapses, where it associates with various vesicular
structures such as clathrin-coated vesicles, endosomal
compartments or caveolae, as well as microtubules (147,

257, 263, 607). This widespread subcellular localization

does not facilitate the definition of its function.
Most proteins were found to interact with NH2-terminal
polyQ-containing huntingtin fragments and, in some cases,
the strength of these interactions has been shown to be
sensitive to the length of the polyQ tract (242, 342).
Huntingtin-interacting proteins cover diverse cellular roles
including clathrin-mediated endocytosis, apoptosis, vesicle
transport, cell signaling, morphogenesis, and transcriptional
regulation (242, 342).
Relevant examples of huntingtin interactors include
huntingtin-associated protein 1 (HAP1), a novel protein with
at least two isoforms (HAP1-A and HAP1-B), which is
expressed in several tissues including the brain and which
interacts with the p150 subunit of dynactin, thus being
involved in intracellular transport. A second protein is
huntingtin-interacting protein 1 (HIP1), which binds to adaptin and clathrin, and is implicated in cytoskeleton
assembly and in endocytosis. Huntingtin binds also to
proteins of the synaptic complex such as protein kinase C
and casein kinase substrate in neurons 1 (PACSIN-1) and
postsynaptic density 95 (PSD95), thus participating in the
regulation of synaptic activity (535). Earlier studies also
showed its ability to interact with glyceraldehyde-3phosphate dehydrogenase (GAPDH) (342).
Wild-type huntingtin interacts with PSD95, a protein located
in the postsynaptic membrane, through its Src homology-3
(SH3) sequence (proline-x-x-proline), regulating the
anchoring of NMDA and kainate (KA) receptors to the
postsynaptic membrane.
Wild-type huntingtin promotes the expression of brain-

derived neurotrophic factor (BDNF) by interacting through

REST-interacting LIM domain protein (RILP) and HAP1
with the repressor element-1 transcription factor/neuronrestrictive silencer factor (REST/NRSF) in the cytoplasm,
and preventing this complex from translocating into the
nucleus and from binding to the repressor element 1/neuronrestrictive silencer element (RE1/NRSE) present in the
promoter of the BDNF gene as well as of many other
neuronal genes (524, 672). Wild-type huntingtin also
promotes the vesicular transport of BDNF along the
microtubules through a mechanism that involves HAP1 and
the p150 subunit of dynactin (202). The interaction of wildtype huntingtin with both HAP1 and mixed-lineage kinase 2
(MLK2) has been shown to promote the expression of
NeuroD (368), a helix-loop-helix transcription factor that is
crucial for the development of the dentate gyrus of the
hippocampus and for the morphogenesis of pancreatic islets.
Wild-type huntingtin also prevents the activation of caspase8 by interacting with HIP1 and preventing the formation of
the
caspase-activating
complex
HIP1-HIP1-protein
interactor (HIPPI) (206).

WhereistheHTTgenelocated?
CytogeneticLocation:4p16.3
MolecularLocationonchromosome4:basepairs3,074,680to
3,243,959

TheHTTgeneislocatedontheshort(p)armofchromosome4
atposition16.3.
More precisely, the HTT gene is located from base pair
3,074,680tobasepair3,243,959onchromosome4.
Thehuntingtinlocusislarge,spanning180kbandconsistingof
67 exons. The huntingtin gene is widely expressed and is
required for normal development. It is expressed as 2
alternativelypolyadenylatedformsdisplayingdifferentrelative
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
transcriptofapproximately10.3kbismorewidelyexpressed.
The genetic defect leading to Huntington's disease may not
necessarily eliminate transcription, but may confer a new
propertyonthemRNAoralterthefunctionoftheprotein.One
candidate is the huntingtinassociated protein1, highly
expressedinbrain,whichhasincreasedaffinityforhuntingtin
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

translationalrepression.
HEAT repeats. HEAT repeats are 40-amino-acid
domains, which fold in two anti- parallel -helices
forming a hairpin (229). Htt features 16 of these
repeats (8; 188; 229), organized in 4 clusters (296).
HEAT may be involved in protein-protein interactions
(9; 217; 240).
Caspase and Calpain Cleavage Sites. These are sites
recognized by proteolytic enzymes (including caspases
1, 3, 6, 7 and 8, calpain and an unidentified aspartic
protease). As a result, a wide range of fragments are
generated (98; 118; 157; 194; 325). The role of Htt
proteolysis for its physiological function is not fully
elucidated. However, full-length mutHtt is less toxic
than its N-terminal fragments (99; 106).

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