Last Updated: March 3, 2023
Introduction to Huntington Disease
Huntington disease is inherited as an autosomal dominant disorder characterized by slowly progressive neurodegeneration associated with choreic movements (abnormal involuntary movements) and dementia. The disease is named after George Huntington who provided the classical account of the disease in 1872. The pathology of HD reveals neurodegeneration in the corpus striatum and shrinkage of the brain.
Molecular Biology of Huntington Disease
HD is caused by expansion of a CAG trinucleotide repeat in the first exon of the huntingtin (HTT) gene. The HTT gene is located on chromosome 4p16.3, spans over 200 kb, and is composed of 67 exons that generate two alternatively polyadenylated mRNAs that are present at different levels in different fetal and adult tissues. These mRNAs encode proteins (in the normal non-triplet expanded state) of 3142 amino acids and 3144 amino acids. Due to individual differences in the number of Gln (Q) residues in the N-terminus of the huntingtin protein the total number of amino acids in unaffected individuals ranges between 3144 and 3172.
The HTT gene is ubiquitously expressed and generates two mRNAs that differ in the length of their 3′ untranslated regions. The CAG repeat resides 17 codons downstream of the initiator AUG codon. The range of CAG repeat size in normal individuals is 6–34 and in affected individuals it is 36–121. The longer the length of the CAG repeat the earlier is the onset of symptoms. However, there is a wide degree of variation in age of onset for any given length of CAG repeat. Thus, the CAG repeat number itself is not predictive for age of onset. The variation in age of onset is related to the effects of other modifying genes, the environment, and the length of the CAG repeat.
In addition, HD exhibits a genetic phenomenon termed “anticipation” which means that the symptoms of the disease appear earlier and are more severe in subsequent generations. This phenomenon is explained by meiotic instability which increases the CAG repeat number and is greater in spermatogenesis than in oogenesis. Therefore, anticipation in mainly observed when the mutation is inherited through the paternal line.
The huntingtin protein is unrelated to any other protein. The polyglutamine tract begins at codon 18 and is followed by a stretch of 29 consecutive proline residues. Wild-type huntingtin protein is found primarily in the cytoplasm with a small percentage being intranuclear. The protein is also found associated with the plasma membrane, the endoplasmic reticulum (ER), the Golgi apparatus, endocytic vesicles, the mitochondria, and microtubules.
In addition to the polyglutamine and polyproline motifs, huntingtin contains 28–36 repeats, termed HEAT motifs, dispersed throughout the length of the protein (HEAT = huntingtin, elongation factor 3, the PR65/A subunit of protein phosphatase 2A and the lipid kinase Tor). The HEAT motif is approximately 50 amino acids in length and is composed of two anti-parallel α-helices that form a hairpin structure. HEAT motifs are involved in protein-protein interactions and serve roles in intracellular transport, chromosome segregation, and microtubule dynamics.
There is no clear nuclear localization signal in huntingtin (although a stretch of basic amino acids from position 1182-1190 can confer nuclear localization when fused to bacterial β-galactosidase) but there is a nuclear export signal in the C-terminus of the protein.
Huntingtin is also fatty acid modified at cysteine 214 (C214) with palmitic acid. The acylation is catalyzed by Hip14 (huntingtin interacting protein 14). This modification regulates huntingtin function and trafficking. The significance of the palmitoylation is demonstrated by the fact that huntingtin protein with an expanded polyglutamine tract is a much poorer substrate for Hip14 than is wild-type protein. Although numerous studies have been aimed at elucidating the exact function of huntingtin, its cellular roles are still poorly defined.
In spite of the lack of a clearly defined role(s) for huntingtin, much has been learned about possible involvement of the protein in numerous processes. Huntingtin is essential for early embryonic development as evidenced by lethality in embryonic mice lacking functional protein. The protein is known to be important in adult neurons and testes for cellular viability. If the level of the protein is reduced it leads to developmental defects and disruptions in iron homeostasis.
Huntingtin also has a role in regulation of transcription through its interaction with numerous transcription factors and other proteins involved in the regulation of mRNA production.
Huntingtin is highly expressed in the presynaptic area of neurons where it interacts with multiple proteins involved in synaptic vesicle exocytosis and recycling.
An additional role for huntingtin in vesicle trafficking is speculated given its localization to endocytic/endosomal vesicles and from its interactions with a number of endocytic/trafficking proteins such as clathrin, dynamin, α-adaptin, Hip1, Hip14 and Hap1 (huntingtin associated protein 1).
Clinical Features of HD
The classical symptoms of Huntington disease consist of progressive dementia, evolving involuntary movements and psychiatric disturbances that include personality changes and mood disorder. Choreiform movements are the most prominent physical abnormality in HD and as such the disease was early on referred to as Huntington chorea. Choreiform movements are characterized by repetitive, brief, irregular, somewhat rapid involuntary movements typically in the face, mouth, trunk, and limbs. The earliest indications of HD is the appearance of spasmodic twitching of the extremities, generally beginning with the fingers. Additional early physical manifestations of HD are clumsiness, hyperreflexia, and eye movement disturbances.
Positron-emission tomography (PET scanning) is used to demonstrate a loss of uptake of glucose in the caudate nuclei and is a valuable indication of affectation in the presymptomatic period in HD patients. There is no cure for HD and all afflicted individuals will succumb to the disease. The age of death in HD is related to the age of onset, i.e. the earlier the onset, the earlier an individual will die.