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GENATLAS PHENOTYPE

last update : 03-09-2020

Symbol	HD
Location	4p16.3
Name	Huntington disease
Corresponding gene	HTT
Main clinical features	onset between the ages of 30 and 40, with changes in personality, a progressive cognitive decline and a spectrum of motor disturbances ranging from abrupt to slow and sustained involuntary movements progressive chorea, rigidity, and dementia, frequently associated with seizures with a characteristic atrophy of the caudate nucleus seen radiographically, prodromal phase of mild psychotic and behavioral symptoms preceding frank chorea by up to 10 years degeneration of spiny neurons in the caudate nucleus linked to disturbed calcium signaling, and abnormal synaptic transmission contributing to the triggering of cell death in later stages of the disease, and early and dramatic destruction selectively of the striatum (PMID: 24324270)) major hallmark of HD is region-specific neuronal degeneration in the striatum and cortex, which subsequently leads to movement disorders and dementia (PMID: 19443488)) in patients, are fund inclusions consisting largely of N-terminal fragments of mutant HTT that are often ubiquitinated, and aggregation propensity increases with polyQ length (PMID: 22801429)) associated to urea cycle deficiency that is an important factor in the pathogenesis of HD and contributes to the disease progression (PMID: 19443488)) associated often with diabetes (PMID: 19628478)) cognitive and neuropsychiatric disturbances that eventually lead to complete disability and death approximately 18–25 years following the onset of the disease (PMID: 19934114)) progressive atrophy of the striatum, caudate nucleus, putamen, globus pallidus and thalamus compared with images of postmortem brain from age-matched control subjects (PMID: 21257639)) progressive neurodegenerative disorder, with marked loss of the major population of neurons in the striatum (medium-sized spiny neurons), which are vulnerable to acute energetic challenge (PMID: 21447599))
Genetic determination	autosomal dominant
Prevalence	estimated to be almost 1 in 10 000 in populations of European descent (PMID: 19934114)
Related entries	infantile forms, with up 60 CGG, in any cases associated with severe atrophy of both the vermis and the cerebellar cortex (PMID: 19253382)
Function/system disorder	neurology
Type	disease

Gene product

Name

huntingtin IT15

Mechanism(s)

Gene mutation	Effect	Comments

repeat expansion	abnormal protein/gain of function	. N terminal highly polymorphic triplet CAG repeat amplification beyond 36 copies, aggregated in neuronal nuclear inclusions and in dystrophic neuritis in the brains with alteration of proteasomal function inducing apoptosis by caspase activation
repeat expansion	abnormal protein/gain of function	mutant progressively accumulates in the nuclei of neurons in brain, ultimately forming visible nuclear inclusions

Remark(s)

expansion of the polymorphic stretch of uninterrupted CAG trinucleotide repeats in exon 1, resulting in a long tract of polyglutamine (polyQ) in the N terminus of the protein huntingtin

expanded stretch of glutamine residues forms aggregates in the nucleus and cytoplasm of affected neurons

pharmacological intervention in MAPK pathways, particularly at the level of ERK activation (ERK activity up-regulation), may be an appropriate approach to HD therapy

mutation responsible of dysfunction of the ubiquitin-proteasome system, leading to accumulation of aggregated fragments of polyglutamine-expanded HTT protein in affected neurons

pathogenic mechanism is likely to be multilayered, involving deregulation of transcriptional and post-transcriptional regulatory pathways combined with other proposed mechanisms such as the triggering of apoptosis and mitochondrial dysfunction to give rise to progressive neurodegeneration

transport deficit in HD can be ameliorated by treating neurons with histone deacetylase 6 (HDAC6) inhibitors (involves tubulin acetylation and the recruitment of molecular motors to MTs but does not involve HTT itself (PMID: 18772195))

pathogenesis might be linked directly, or indirectly, to a perturbation of mitochondria function (overexpression of HTT proteins containing polyglutamine repeats increases oxidative stress-induced mitochondrial fragmentation ) (PMID: 18772195))

cleavage of huntingtin at residue Arg167 may mediate mutant huntingtin toxicity in Huntington disease (PMID: 19204007))

loss of wild-type huntingtin function in HD and potential disruption of cholesterol homeostasis in the brain may be important for the progression of HD since cholesterol is important for synaptogenesis, neurite outgrowth and neurotransmitter release, processes which are seen to be impaired in HD (PMID: 19451134))

mutant Htt protein forms aggregates in the brain and several peripheral tissues (e.g. the liver) and causes devastating neuronal degeneration (PMID: 19443488))

novel therapeutic pathway of A2A receptors in HD and further strengthen the concept that the A2A receptor can be a drug target in treating HD (PMID: 19443488))

mutant huntingtin disrupts intracellular transport and insulin secretion by direct interference with microtubular beta-tubulin (PMID: 19628478))

identification of novel striatal-enriched genes with altered expression in HD offers new avenues of study, leading towards a better understanding of specific pathways involved in the selective degeneration of striatal neurons in HD (PMID: 19934114))

mutant huntingtin selectively suppresses POU3F2 transcription factor to mediate hypothalamic cell dysfunction (PMID: 20185558))

mitochondrial dysfunction plays a critical role in the pathogenesis of HD (PMID: 20660112))

fisetin, resveratrol and related compounds might be useful for the treatment of HD by virtue of their unique ability to activate ERK (PMID: 20952447))

increased mutant Htt oligomers may be involved in mitochondrial fragmentation, abnormal mitochondrial dynamics and oxidative DNA damage in neurons

mutant HTT interacts aberrantly with numerous partners, led to the concept that polyQ expansion undergoes a toxic conformational change that affects interactions between HTT and partners (PMID: 21518730))

mt HTT affects processes such as ER/Golgi vesicular trafficking, autophagy and ER calcium homeostasis (PMID: 21659333))

reducing mitochondrial Ca(2+) uptake could be a therapeutic strategy for HD (PMID: 23250749))

structural and functional alterations of Complex 2 induced by mutant Htt may play a critical role in the degeneration of striatal neurons in HD and mitochondrial-targeted therapies may be useful in its treatment (PMID: 23720495))

overexpression of the N-terminal fragment of mutant HTT decreased the velocity of mitochondrial axonal transport and mitochondrial mobility in neurons regardless of whether aggregates were formed (PMID: 24362588))

only the expanded length of the HTT CAG repeat has significant power for predicting both age at onset and age at death but that remaining variance in these measures is unexplained by the CAG mutation and must be due to other causes (PMID: 26849111))

FAN1 is the HD modifier gene at the 15q13.2–13.3 locus and reinforces the view that each of the DNA maintenance genes at or near modifier signals on chromosomes 2 (PMS1), 3 (MLH1), 5 (MSH3), 7 (PMS2), and 19 (LIG1) will prove to be the respective sources of HD modification through influences on somatic expansion of the CAG repeat (PMID: 32589923))

Genotype/Phenotype correlations

somatic instability was found to be a significant predictor of onset age, with larger repeat length gains associated with earlier disease onset (PMID: 19465745))