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The Relationship Between Huntingtin and Huntington Disease

Overview of the possible causes and effects of Huntington Disease.

Gathered information worldwide has revealed some patterns in HD frequency distribution. The prevalence of HD is particularly rare in Japan and Finland. On the other hand, the disease is found at relatively high frequencies in various parts of the world. The regions encompass Northern and Southern Europe (4 to 8 per 100,000), parts of India and Central Asia. HD cases in European American also show frequencies and origins comparable to those in the ancestor groups in Europe. The disease is likely caused by independent mutations but the relative high prevalence in European populations seems to result from a very small number of mutations in early ancestors. Regardless of origins and ethnicity, the abnormality of CAG repeat length, however, shows to be universal and characteristic of HD compared to other neurodegenerative disorders.

Huntington disease (HD) is caused by a dominant mutant allele of huntingtin gene, also known as IT15 gene. The gene resides at locus 4p16.3 on the short arm of Chromosome 4. Its locus was initially discovered by large-scale pedigree analysis specifically U.S.- Venezuela HD project, which located the allele 4 cM near the eighth polymorphic marker G8 (D4S10). Later studies using linkage disequilibrium determined the allele most likely to lie within a 2 Mb region nearer to G8/D4S10 than to the telomere.

The mutation that causes Huntington disease is the increase in the number of CAG repeats in the ORF of exon 1 of the huntingtin gene. Normally, the unaffected range of CAG repeats lies within 6 to 35 repeats. Those alleles with more than 40 repeats show complete penetrance within normal lifespan. When alleles contain between 36 and 39 repeats, the carriers have a small risk of developing Huntington disease. It is supported by the fact that few HD case has been documented with the intermediate range of CAG repeat size and some elderly unaffected survive. The evidence favors the idea of reduced penetrance of HD in the presence of 36-39 repeats in genome. In addition, the trinucleotide repeat size is found to be inversely related to the age of HD onset. With 70 or more repeats, individuals show complete penetrance with development of the juvenile onset. It is found that homozygous individuals for HD show no significant difference in the age and onset of the disease. However, their disease progression is much more severe that those heterozygous for CAG expansion.

The length of CAG repeats varies as they are transmitted from parents to progeny. It has been found that children are more likely to inherit large expansions of CAG from affected paternal parents. In fact, 80% of junvenile HD with large expansion is transmitted from paternal parents. In addition, germline cells from non-HD individuals show little CAG repeat instability while HD alleles have been found to undergo repeat expansion in germline cells, which transmit it to the next generation. Alleles of the intermediate CAG range also show signs of the instability and children of the carrier of these alleles have either reduced or increased risk of developing HD. There has been discovered that the intermediate ranged alleles are source of new mutations that cause HD. In males carrying intermediate alleles, the number of sperms that have CAG expansions is directly related to the size of CAG repeat. Spermatogenesis likely involves some mechanism to increase the CAG repeat but the mechanism has not yet been unveiled particularly at the molecular level. On the other hand, no such evidence has been found so far that relates to repeat expansion in female transmission of intermediate alleles.

Not all features of Huntington disease, however, exclusively are attributed to mutations in CAG repeat in HD gene. There have been reported a small portion of HD cases in which mutations reside in non-huntingtin genes, accounting for a small portion of HD patients. The most important variants of HD disease are those showing significant similarity in signs and symptoms with Huntington disease. Those disorders are designated as Huntington disease like (HDL) syndromes. Those characterized phenocopies of HD so far include mutant prion protein gene (HDL1) on chromosome 20p12, the junctophilin 3 gene (HDL2) on chromosome 16q24.3, the TATA box encoding gene (HDL4/SCA17) on chromosome 6q27, and HDL3 on chromosome 4p15.3. The three former ones are autosomal dominant alleles while the last is an autosomal recessive.

There has been so far little research on the influence of environmental factors on Huntington Disease symptom variation with concrete evidence. One study has investigated the correlation between slow progression and some common factors on 42 patients that have been carefully observed. It results indicate slow progression link to late age of onset, high body mass index and male gender. The most significant results, however, comes from data provided by the U.S.-Venezuela collaborative research project from 1981 to 2001. One important study used available data related to 18,149 Venezuelan individuals of 83 kindreds that Huntington Disease is present. Through extensive analysis, researchers of the study have discovered that 59% of remaining variability of age of onset can be accounted for by genetics and shared environment other than the variance of trinucleotide repeat size. Addition research has revealed some of the genetic factors apart from the size of CAG repeats, it also has been found to associate with GluR6 kainate receptor locus. The protein it codes for mediates amino acid excitotoxicity, which has been proved to cause similar pathology to HD. The variation in two similar genes GRIN2A and GRIN 23 which codes for NHuntington Disease variation other than trinucleotide repeat expansion.
-Methyl-D-aspartate (NMDA) receptor NR2A and NR2B also correlates to the age of HD onset. However, further studies have been so far inadequate to isolate and characterize many of genetic and shared environmental factors contributing to

Up to date, only available therapies can only alleviate HD symptoms in patients and no cure has been developed. Beneficial results have been obtained in Huntington Disease lab animals treated with some substances. Some increases expression of neuroprotective genes, some inhibit apoptosis or the formation of peptide aggregates. However, a survey of the 24 best studies in treating HD symptoms by Bonelli et al. points out that they fail to produce positive results to apply in clinical treatment. The authors, upon the analysis, recommend a set of treatments that have shown positive effects on patient (Table 1). Recently, the research, conducted by Harper et al., applying interference RNA produces a promising result. In mouse cell culture, they have obtained reduced mutant hungtintin mRNA and production expression targeted by iRNA. The gene silencing ameliorates behavioral and neuropathological symptoms linked to Huntington Disease. The study shows a promising potential of an RNAi therapy on treating Huntington Disease.

Table 1. Recommended treatment regime.

Disorder

Treatment

Chorea (mild to moderation)

No medication

Chorea (severe)

Olanzapine

Bradykinesia/rigor

Physiotherapy

Dystonia/gait disorder

Physiotherapy

Dysphagia/Dysartria

Speech therapy

Impaired fine motor tasks

Occupational therapy

Depression

Selective serotonin reuptake inhibitor Mirtazapine

Psychotherapy

Aggression/psychosis

Risperidone

Olanzapine

Dementia/apathy

Memory training, Occupational therapy, Psychosocial intergration

Source: Bonelli et al. 2004.

The gene responsible for Huntington Disease has long been known and its genetics has been vigorously studied with significant results. Because Huntington Disease is still incurable, genetic testing is essential to those at risk either ready for proactive treatment or complete relief from such lethal disorder as Huntington Disease. Genetic testing is highly accuracy because Huntington Disease is specifically traced to the abnormal increase of CAG tracts in IT15. However, these tests only apply to individuals bearing CAG repeat sizes in the normal and affected range and unable to determine those in the intermediate range of 36-39 CAG repeats. Such result can only inform the carriers about the risk of their children developing the disease. If an individual wishes to know whether their children would have the mutant allele, amniocentensis and practice of chorionic villus samples are the most recommended with highly accuracy diagnosis.

Genetic testing even though provides accurate information about the disease condition, it is followed by psychological, ethical and social impacts and consequences . Presymptomatic people with 50% risk can suffer high levels of anxiety. Young people tend to make decisions about long-term education, marriage and children. Older parents, on the other hand, are worried about fears and guilt passing on the disease allele to their children and grandchildren. People at risk are generally not willing to proceed with genetic testing when reached by testing centers or registries and only 10%-20% are. Psychological impacts do not significantly differ in carriers and non-carriers in the long term rather than in the short term. Reactions in people tested generally correlate to linkage analysis test and proactive seeking for genetic testing while mutation detection programs relate to higher levels of stress before and after testing. It has been recorded that unaffected carriers suffer a certain degree of guilt because they will not develop Huntington Disease but possibly pass on the disease to their children, particular if they expect to eliminate that risk by testing. People that prefer not to under testing, would rather accept the uncertainty of staying at risk and avoid consequences of genetic discrimination from employers (job loss or decline) and insurance companies (denying to insurance contract) and social attitudes. The social response to \ Huntington Disease affected people is dictated by the characteristics of a certain social system, which requires non-genetics research to understand and evaluate. In addition, results of HD testing produce information about related families, communities, minority groups or race which can lead to the stigmatization of the entire group. There is a considerable consent that research acceptability must be accommodated with identified populations. Because complicated situations might be produced by genetic testing results of Huntington Disease, genetic counseling for Huntington Disease is necessary for those at risk to make informed decision.

So far, Huntington Disease has been attributabled to CAG repeat expansions in gene IT15 or huntingtin. The mutations result in a polyglutamine stretch expanded at N-terminus of the protein. Aggregates containing amyloidal fibers from ubiquitinated degraded fragments of the mutant protein in the neuron nuclear damage cells and cause immature apoptosis. That affects predominantly affected medium spiny projection neurons in striatum, other basal ganglia, cortex and other regions in which medium spiny projection cells are most affected. The levels of huntingtin expression in neuronal cells are similar while vulnerability is generally high in MSNs. Shelburne et al. (2020) recently sheds light the patterns of neuron loss and the instability of CAG repeat size throughout the disease progression of HD. The study is carried out on human and mouse brain tissue. Both in human and mouse, CAG repeat tracts show significant levels of length variability before appreciable cell loss. Repeat gain occurs early and continues to build up in the disease progression. Repeat length has been found longer in neuron tissues (rich with MSNs) than in glia, as great as discovered in germ line cells, which correlates to substantial vulnerability of strial MSNs. The research helps explain CAG repeat gain in somatic neurons over time may be responsible the progressive nature of Huntington Disease development. The mechanism of producing mutation instability in non-dividing cells opens up a new dimension in researching Huntington disease. The new finding demands a new mechanism explanation to increase DNA segments with no replication involved.

Another fascinating discovery in 2020 has connected huntingtin gene regulation with gene p53 gene. p53 has long known as one of the most important tumor suppressor in cancer prevention. Studies in the late 20th and early 21st centuries have revealed additional roles of p53 as a central integrator of cellular responses and stress response. Adding to the list,Feng et al. (2020) have found p53 role in modulating the gene expression of huntingtin. In both human and murine cells, activated p53, as a positive modifier, can increase the gene expression of normal huntingtinin vivo and in vitro. The researchers expect the same interaction of mutant huntingtin causing Huntington Disease because mutations only affect the length of CAG repeats of exon 1 but not in the controlling regions. The interaction between two genes has also been found in the striatal and cortical tissues in mouse which are most significantly affected in Huntington Disease. The results lead them to speculate that any environmental factor such as hypoxia or DNA damage that activates p53 would increase the presence of mutant hungtingtin proteins and accelerate the deleterious progression of Huntington Disease. In conclusion, the study opens a new opportunity to study in depth the role of p53 in the progressive development of Huntington Disease.

Sources Cited:

Harper P.S. 1992. The epidemiology of Huntington's disease. Hum. Genet.89(4): 365-376.

Kremer B., Goldberg P., Andrew S. E., Theilmann J., Telenius H., Zeisler J., Squitieri F., Lin B., Bassett A., Almqvist E., Bird T. D., and Hayden M. R. 1994. A worldwide study of the Huntington's disease mutation: the sensitivity and specificity of measuring CAG repeats.New Eng. J. Med. 330: 1401-1406.

McNeil S.M., Novelleto A., Srinidhi J., Barnes G., Kornbluth I., Altherr M.R., Wasmuth J.J., Gusella J.F., MacDonald M.E. and Myers R.H. 1997. Reduced penetrance of the Huntington's disease mutation. Hum. Mol. Genet.6: 775-779.

U.S. National library of Medicine. Genetic conditions: Huntington disease. 2020 Oct [cited 2020 Oct 31]. Available from

Vousden K.H and Lane D.P. 2020. p53 in health and disease (Article series: Mechanisms of disease). Nat. Rev. Mol. Cell Biol.8: 275-283.