Journal of Huntington's Disease - Volume 10, issue 1

Authors: Leavitt, Blair R. | Thompson, Leslie M.

Article Type: Editorial

DOI: 10.3233/JHD-219002

Citation: Journal of Huntington's Disease, vol. 10, no. 1, pp. 1-1, 2021

Authors: Jones, Lesley | Wheeler, Vanessa C. | Pearson, Christopher E.

Article Type: Introduction

Keywords: Repeat expansion disorders, somatic repeat expansion, Huntington’s disease, short tandem repeat, DNA repair, genetic modifiers of Huntington’s disease, neurodegeneration, drug targets

DOI: 10.3233/JHD-219001

Citation: Journal of Huntington's Disease, vol. 10, no. 1, pp. 3-5, 2021

Authors: Monckton, Darren G.

Article Type: Review Article

Abstract: The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington’s disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that …is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway. These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention. Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders. Show more

Keywords: Somatic expansion, anticipation, CAG repeat, genotype to phenotype, mutation, DNA mismatch repair

DOI: 10.3233/JHD-200429

Citation: Journal of Huntington's Disease, vol. 10, no. 1, pp. 7-33, 2021

Authors: Hong, Eun Pyo | MacDonald, Marcy E. | Wheeler, Vanessa C. | Jones, Lesley | Holmans, Peter | Orth, Michael | Monckton, Darren G. | Long, Jeffrey D. | Kwak, Seung | Gusella, James F. | Lee, Jong-Min

Article Type: Review Article

Abstract: Historically, Huntington’s disease (HD; OMIM #143100) has played an important role in the enormous advances in human genetics seen over the past four decades. This familial neurodegenerative disorder involves variable onset followed by consistent worsening of characteristic abnormal movements along with cognitive decline and psychiatric disturbances. HD was the first autosomal disease for which the genetic defect was assigned to a position on the human chromosomes using only genetic linkage analysis with common DNA polymorphisms. This discovery set off a multitude of similar studies in other diseases, while the HD gene, later renamed HTT , and its vicinity in …chromosome 4p16.3 then acted as a proving ground for development of technologies to clone and sequence genes based upon their genomic location, with the growing momentum of such advances fueling the Human Genome Project. The identification of the HD gene has not yet led to an effective treatment, but continued human genetic analysis of genotype-phenotype relationships in large HD subject populations, first at the HTT locus and subsequently genome-wide, has provided insights into pathogenesis that divide the course of the disease into two sequential, mechanistically distinct components. Show more

Keywords: Huntington disease, genetics, genotype-phenotype correlation, genetic association, modifier gene, trinucleotide repeat expansion

DOI: 10.3233/JHD-200427

Citation: Journal of Huntington's Disease, vol. 10, no. 1, pp. 35-51, 2021

Authors: Ciosi, Marc | Cumming, Sarah A. | Chatzi, Afroditi | Larson, Eloise | Tottey, William | Lomeikaite, Vilija | Hamilton, Graham | Wheeler, Vanessa C. | Pinto, Ricardo Mouro | Kwak, Seung | Morton, A. Jennifer | Monckton, Darren G.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of the HTT CAG repeat. Affected individuals inherit ≥36 repeats and longer alleles cause earlier onset, greater disease severity and faster disease progression. The HTT CAG repeat is genetically unstable in the soma in a process that preferentially generates somatic expansions, the proportion of which is associated with disease onset, severity and progression. Somatic mosaicism of the HTT CAG repeat has traditionally been assessed by semi-quantitative PCR-electrophoresis approaches that have limitations (e.g., no information about sequence variants). Genotyping-by-sequencing could allow for some of …these limitations to be overcome. Objective: To investigate the utility of PCR sequencing to genotype large (>50 CAGs) HD alleles and to quantify the associated somatic mosaicism. Methods: We have applied MiSeq and PacBio sequencing to PCR products of the HTT CAG repeat in transgenic R6/2 mice carrying ∼55, ∼110, ∼255 and ∼470 CAGs. For each of these alleles, we compared the repeat length distributions generated for different tissues at two ages. Results: We were able to sequence the CAG repeat full length in all samples. However, the repeat length distributions for samples with ∼470 CAGs were biased towards shorter repeat lengths. Conclusion: PCR sequencing can be used to sequence all the HD alleles considered, but this approach cannot be used to estimate modal allele size or quantify somatic expansions for alleles ⪢250 CAGs. We review the limitations of PCR sequencing and alternative approaches that may allow the quantification of somatic contractions and very large somatic expansions. Show more

Keywords: Somatic mosaicism, huntingtin, Huntington disease, repeat expansion, parallel sequencing

DOI: 10.3233/JHD-200433

Citation: Journal of Huntington's Disease, vol. 10, no. 1, pp. 53-74, 2021

Authors: Iyer, Ravi R. | Pluciennik, Anna

Article Type: Review Article

Abstract: DNA mismatch repair (MMR) is a highly conserved genome stabilizing pathway that corrects DNA replication errors, limits chromosomal rearrangements, and mediates the cellular response to many types of DNA damage. Counterintuitively, MMR is also involved in the generation of mutations, as evidenced by its role in causing somatic triplet repeat expansion in Huntington’s disease (HD) and other neurodegenerative disorders. In this review, we discuss the current state of mechanistic knowledge of MMR and review the roles of key enzymes in this pathway. We also present the evidence for mutagenic function of MMR in CAG repeat expansion and consider mechanistic hypotheses …that have been proposed. Understanding the role of MMR in CAG expansion may shed light on potential avenues for therapeutic intervention in HD. Show more

Keywords: DNA mismatch repair, Huntington’s disease, DNA structures, triplet repeat instability, somatic expansion, neurodegeneration

DOI: 10.3233/JHD-200438

Citation: Journal of Huntington's Disease, vol. 10, no. 1, pp. 75-94, 2021

Authors: Deshmukh, Amit L. | Porro, Antonio | Mohiuddin, Mohiuddin | Lanni, Stella | Panigrahi, Gagan B. | Caron, Marie-Christine | Masson, Jean-Yves | Sartori, Alessandro A. | Pearson, Christopher E.

Article Type: Review Article

Abstract: FAN1 encodes a DNA repair nuclease. Genetic deficiencies, copy number variants, and single nucleotide variants of FAN1 have been linked to karyomegalic interstitial nephritis, 15q13.3 microdeletion/microduplication syndrome (autism, schizophrenia, and epilepsy), cancer, and most recently repeat expansion diseases. For seven CAG repeat expansion diseases (Huntington’s disease (HD) and certain spinocerebellar ataxias), modification of age of onset is linked to variants of specific DNA repair proteins. FAN1 variants are the strongest modifiers. Non-coding disease-delaying FAN1 variants and coding disease-hastening variants (p.R507H and p.R377W) are known, where the former may lead to increased FAN1 levels and the latter …have unknown effects upon FAN1 functions. Current thoughts are that ongoing repeat expansions in disease-vulnerable tissues, as individuals age, promote disease onset. Fan1 is required to suppress against high levels of ongoing somatic CAG and CGG repeat expansions in tissues of HD and FMR1 transgenic mice respectively, in addition to participating in DNA interstrand crosslink repair. FAN1 is also a modifier of autism, schizophrenia, and epilepsy. Coupled with the association of these diseases with repeat expansions, this suggests a common mechanism, by which FAN1 modifies repeat diseases. Yet how any of the FAN1 variants modify disease is unknown. Here, we review FAN1 variants, associated clinical effects, protein structure, and the enzyme’s attributed functional roles. We highlight how variants may alter its activities in DNA damage response and/or repeat instability. A thorough awareness of the FAN1 gene and FAN1 protein functions will reveal if and how it may be targeted for clinical benefit. Show more

Keywords: DNA repair, FAN1, Huntington’s disease, karyomegalic interstitial nephritis, modifier, nuclease, repeat instability

DOI: 10.3233/JHD-200448

Citation: Journal of Huntington's Disease, vol. 10, no. 1, pp. 95-122, 2021

Authors: Wheeler, Vanessa C. | Dion, Vincent

Article Type: Review Article

Abstract: At fifteen different genomic locations, the expansion of a CAG/CTG repeat causes a neurodegenerative or neuromuscular disease, the most common being Huntington’s disease and myotonic dystrophy type 1. These disorders are characterized by germline and somatic instability of the causative CAG/CTG repeat mutations. Repeat lengthening, or expansion, in the germline leads to an earlier age of onset or more severe symptoms in the next generation. In somatic cells, repeat expansion is thought to precipitate the rate of disease. The mechanisms underlying repeat instability are not well understood. Here we review the mammalian model systems that have been used to study …CAG/CTG repeat instability, and the modifiers identified in these systems. Mouse models have demonstrated prominent roles for proteins in the mismatch repair pathway as critical drivers of CAG/CTG instability, which is also suggested by recent genome-wide association studies in humans. We draw attention to a network of connections between modifiers identified across several systems that might indicate pathway crosstalk in the context of repeat instability, and which could provide hypotheses for further validation or discovery. Overall, the data indicate that repeat dynamics might be modulated by altering the levels of DNA metabolic proteins, their regulation, their interaction with chromatin, or by direct perturbation of the repeat tract. Applying novel methodologies and technologies to this exciting area of research will be needed to gain deeper mechanistic insight that can be harnessed for therapies aimed at preventing repeat expansion or promoting repeat contraction. Show more

Keywords: Huntington’s disease, myotonic dystrophy 1, DNA repair, trinucleotide repeat instability, mismatch repair

DOI: 10.3233/JHD-200426

Citation: Journal of Huntington's Disease, vol. 10, no. 1, pp. 123-148, 2021

Authors: Zhao, Xiaonan | Kumari, Daman | Miller, Carson J. | Kim, Geum-Yi | Hayward, Bruce | Vitalo, Antonia G. | Pinto, Ricardo Mouro | Usdin, Karen

Article Type: Review Article

Abstract: Huntington’s disease (HD) is one of a large group of human disorders that are caused by expanded DNA repeats. These repeat expansion disorders can have repeat units of different size and sequence that can be located in any part of the gene and, while the pathological consequences of the expansion can differ widely, there is evidence to suggest that the underlying mutational mechanism may be similar. In the case of HD, the expanded repeat unit is a CAG trinucleotide located in exon 1 of the huntingtin (HTT ) gene, resulting in an expanded polyglutamine tract in the huntingtin protein. …Expansion results in neuronal cell death, particularly in the striatum. Emerging evidence suggests that somatic CAG expansion, specifically expansion occurring in the brain during the lifetime of an individual, contributes to an earlier disease onset and increased severity. In this review we will discuss mouse models of two non-CAG repeat expansion diseases, specifically the Fragile X-related disorders (FXDs) and Friedreich ataxia (FRDA). We will compare and contrast these models with mouse and patient-derived cell models of various other repeat expansion disorders and the relevance of these findings for somatic expansion in HD. We will also describe additional genetic factors and pathways that modify somatic expansion in the FXD mouse model for which no comparable data yet exists in HD mice or humans. These additional factors expand the potential druggable space for diseases like HD where somatic expansion is a significant contributor to disease impact. Show more

Keywords: Huntington’s disease, Friedreich ataxia, Fragile X-related disorders, FMR1-associated disorders, trinucleotide repeat instability, mismatch repair, base excision repair, double-strand break repair, non-homologous end-joining

DOI: 10.3233/JHD-200423

Citation: Journal of Huntington's Disease, vol. 10, no. 1, pp. 149-163, 2021

Authors: Maiuri, Tamara | Hung, Claudia L.K. | Suart, Celeste | Begeja, Nola | Barba-Bazan, Carlos | Peng, Yi | Savic, Natasha | Wong, Timothy | Truant, Ray

Article Type: Review Article

Abstract: The use of genome wide association studies (GWAS) in Huntington’s disease (HD) research, driven by unbiased human data analysis, has transformed the focus of new targets that could affect age at onset. While there is a significant depth of information on DNA damage repair, with many drugs and drug targets, most of this development has taken place in the context of cancer therapy. DNA damage repair in neurons does not rely on DNA replication correction mechanisms. However, there is a strong connection between DNA repair and neuronal metabolism, mediated by nucleotide salvaging and the poly ADP-ribose (PAR) response, and this …connection has been implicated in other age-onset neurodegenerative diseases. Validation of leads including the mismatch repair protein MSH3, and interstrand cross-link repair protein FAN1, suggest the mechanism is driven by somatic CAG instability, which is supported by the protective effect of CAA substitutions in the CAG tract. We currently do not understand: how somatic instability is triggered; the state of DNA damage within expanding alleles in the brain; whether this damage induces mismatch repair and interstrand cross-link pathways; whether instability mediates toxicity, and how this relates to human ageing. We discuss DNA damage pathways uncovered by HD GWAS, known roles of other polyglutamine disease proteins in DNA damage repair, and a panel of hypotheses for pathogenic mechanisms. Show more

Keywords: Huntington’s disease, somatic expansion, genome wide analysis studies, disease modifiers, N6-furfuryladenine

DOI: 10.3233/JHD-200414

Citation: Journal of Huntington's Disease, vol. 10, no. 1, pp. 165-173, 2021

Authors: Donaldson, Jasmine | Powell, Sophie | Rickards, Nadia | Holmans, Peter | Jones, Lesley

Article Type: Review Article

Abstract: Huntington’s disease (HD) (OMIM 143100) is caused by an expanded CAG repeat tract in the HTT gene. The inherited CAG length is known to expand further in somatic and germline cells in HD subjects. Age at onset of the disease is inversely correlated with the inherited CAG length, but is further modulated by a series of genetic modifiers which are most likely to act on the CAG repeat in HTT that permit it to further expand. Longer repeats are more prone to expansions, and this expansion is age dependent and tissue-specific. Given that the inherited tract expands through life …and most subjects develop disease in mid-life, this implies that in cells that degenerate, the CAG length is likely to be longer than the inherited length. These findings suggest two thresholds— the inherited CAG length which permits further expansion, and the intracellular pathogenic threshold, above which cells become dysfunctional and die. This two-step mechanism has been previously proposed and modelled mathematically to give an intracellular pathogenic threshold at a tract length of 115 CAG (95% confidence intervals 70– 165 CAG). Empirically, the intracellular pathogenic threshold is difficult to determine. Clues from studies of people and models of HD, and from other diseases caused by expanded repeat tracts, place this threshold between 60– 100 CAG, most likely towards the upper part of that range. We assess this evidence and discuss how the intracellular pathogenic threshold in manifest disease might be better determined. Knowing the cellular pathogenic threshold would be informative for both understanding the mechanism in HD and deploying treatments. Show more

Keywords: DNA repair, DNA repeat expansion, Huntington’s disease, spinocerebellar ataxias, trinucleotide repeat

DOI: 10.3233/JHD-200445

Citation: Journal of Huntington's Disease, vol. 10, no. 1, pp. 175-202, 2021

Authors: Benn, Caroline L. | Gibson, Karl R. | Reynolds, David S.

Article Type: Review Article

Abstract: DNA damage repair (DDR) mechanisms have been implicated in a number of neurodegenerative diseases (both genetically determined and sporadic). Consistent with this, recent genome-wide association studies in Huntington’s disease (HD) and other trinucleotide repeat expansion diseases have highlighted genes involved in DDR mechanisms as modifiers for age of onset, rate of progression and somatic instability. At least some clinical genetic modifiers have been shown to have a role in modulating trinucleotide repeat expansion biology and could therefore provide new disease-modifying therapeutic targets. In this review, we focus on key considerations with respect to drug discovery and development using DDR mechanisms …as a target for trinucleotide repeat expansion diseases. Six areas are covered with specific reference to DDR and HD: 1) Target identification and validation; 2) Candidate selection including therapeutic modality and delivery; 3) Target drug exposure with particular focus on blood-brain barrier penetration, engagement and expression of pharmacology; 4) Safety; 5) Preclinical models as predictors of therapeutic efficacy; 6) Clinical outcome measures including biomarkers. Show more

Keywords: Huntingtin (HTT), CAG repeat, polyglutamine (polyQ), somatic instability, mismatch repair (MMR), PARP, ATM

DOI: 10.3233/JHD-200421

Citation: Journal of Huntington's Disease, vol. 10, no. 1, pp. 203-220, 2021