Genetic modifiers of Huntington’s disease differentially influence motor and cognitive domains

AbstractGenome-wide association studies (GWAS) of Huntington’s disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat with subsequent triggering of neuronal damage. The largest studies have been limited to HD individuals with a rater-estimated age at motor onset. To capitalize on the wealth of phenotypic data in several large HD natural history studies, we have performed algorithmic prediction using common motor and cognitive measures to predict age at other disease landmarks as additional phenotypes for GWAS. Combined with imputation using the Trans-Omics for Precision Medicine reference panel, predictions using integrated measures provided objective landmark phenotypes with greater power to detect most modifier loci. Importantly, substantial differences in the relative modifier signal across loci, highlighted by comparing common modifiers at MSH3 and FAN1, revealed that individual modifier effects can act preferentially in the motor or cognitive domains. Individual components of the DNA maintenance modifier mechanisms may therefore act differentially on the neuronal circuits underlying the corresponding clinical measures. In addition, we identified new modifier effects at the PMS1 and PMS2 loci and implicated a potential new locus on chromosome 7. These findings indicate that broadened discovery and characterization of HD genetic modifiers based on additional quantitative or qualitative phenotypes offers not only the promise of in-human validated therapeutic targets, but also a route to dissecting the mechanisms and cell types involved in both the somatic instability and toxicity components of HD pathogenesis.

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FAN1 nuclease activity affects CAG expansion and age at onset of Huntington’s disease

10.1101/2021.04.13.439716 ◽

2021 ◽

Author(s):

Branduff McAllister ◽

Jasmine Donaldson ◽

Caroline S. Binda ◽

Sophie Powell ◽

Uroosa Chughtai ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Cell Model ◽

Association Studies ◽

Age At Onset ◽

Nuclease Activity ◽

Cag Repeat ◽

Genome Wide Association Studies ◽

Knock Out ◽

Cag Expansion

SummaryThe age at onset of motor symptoms in Huntington’s disease (HD) is driven by HTT CAG repeat length but modified by other genes. We used exome sequencing of 683 HD patients with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We identified damaging coding variants in candidate modifier genes from prior genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier onset HD. Nuclease activities of these variants correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion comparable to those observed with complete FAN1 knock out. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.

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Genetics of disease severity in multiple sclerosis, Alzheimer’s disease, and Huntington’s disease: rejuvenating genome-wide association studies

Journal of Neurology ◽

10.1007/s00415-017-8584-y ◽

2017 ◽

Vol 264 (9) ◽

pp. 2040-2042

Author(s):

James Hrastelj ◽

Neil Robertson

Keyword(s):

Multiple Sclerosis ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Severity ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide

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Gametic but not somatic instability of CAG repeat length in Huntington's disease.

Journal of Medical Genetics ◽

10.1136/jmg.30.12.982 ◽

1993 ◽

Vol 30 (12) ◽

pp. 982-986 ◽

Cited By ~ 127

Author(s):

M E MacDonald ◽

G Barnes ◽

J Srinidhi ◽

M P Duyao ◽

C M Ambrose ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Repeat Length ◽

Cag Repeat ◽

Somatic Instability

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Subcellular Localization And Formation Of Huntingtin Aggregates Correlates With Symptom Onset And Progression In A Huntington’S Disease Model

Brain Communications ◽

10.1093/braincomms/fcaa066 ◽

2020 ◽

Vol 2 (2) ◽

Cited By ~ 2

Author(s):

Christian Landles ◽

Rebecca E Milton ◽

Nadira Ali ◽

Rachel Flomen ◽

Michael Flower ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Model ◽

Repeat Expansion ◽

Cag Repeat ◽

Genetic Modifiers ◽

Stage Disease ◽

Progression Of Disease ◽

Exon 1 ◽

End Stage

Abstract Huntington’s disease is caused by the expansion of a CAG repeat within exon 1 of the HTT gene, which is unstable, leading to further expansion, the extent of which is brain region and peripheral tissue specific. The identification of DNA repair genes as genetic modifiers of Huntington’s disease, that were known to abrogate somatic instability in Huntington’s disease mouse models, demonstrated that somatic CAG expansion is central to disease pathogenesis, and that the CAG repeat threshold for pathogenesis in specific brain cells might not be known. We have previously shown that the HTT gene is incompletely spliced generating a small transcript that encodes the highly pathogenic exon 1 HTT protein. The longer the CAG repeat, the more of this toxic fragment is generated, providing a pathogenic consequence for somatic expansion. Here, we have used the R6/2 mouse model to investigate the molecular and behavioural consequences of expressing exon 1 HTT with 90 CAGs, a mutation that causes juvenile Huntington’s disease, compared to R6/2 mice carrying ∼200 CAGs, a repeat expansion of a size rarely found in Huntington’s disease patient’s blood, but which has been detected in post-mortem brains as a consequence of somatic CAG repeat expansion. We show that nuclear aggregation occurred earlier in R6/2(CAG)90 mice and that this correlated with the onset of transcriptional dysregulation. Whereas in R6/2(CAG)200 mice, cytoplasmic aggregates accumulated rapidly and closely tracked with the progression of behavioural phenotypes and with end-stage disease. We find that aggregate species formed in the R6/2(CAG)90 brains have different properties to those in the R6/2(CAG)200 mice. Within the nucleus, they retain a diffuse punctate appearance throughout the course of the disease, can be partially solubilized by detergents and have a greater seeding potential in young mice. In contrast, aggregates from R6/2(CAG)200 brains polymerize into larger structures that appear as inclusion bodies. These data emphasize that a subcellular analysis, using multiple complementary approaches, must be undertaken in order to draw any conclusions about the relationship between HTT aggregation and the onset and progression of disease phenotypes.

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Promotion of somatic CAG repeat expansion by Fan1 knock-out in Huntington’s disease knock-in mice is blocked by Mlh1 knock-out

Human Molecular Genetics ◽

10.1093/hmg/ddaa196 ◽

2020 ◽

Vol 29 (18) ◽

pp. 3044-3053 ◽

Cited By ~ 2

Author(s):

Jacob M Loupe ◽

Ricardo Mouro Pinto ◽

Kyung-Hee Kim ◽

Tammy Gillis ◽

Jayalakshmi S Mysore ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Genetic Interaction ◽

Age At Onset ◽

Repeat Expansion ◽

Cag Repeat ◽

Genome Wide Association Studies ◽

Knock Out ◽

Cag Repeat Expansion ◽

Dna Instability

Abstract Recent genome-wide association studies of age-at-onset in Huntington’s disease (HD) point to distinct modes of potential disease modification: altering the rate of somatic expansion of the HTT CAG repeat or altering the resulting CAG threshold length-triggered toxicity process. Here, we evaluated the mouse orthologs of two HD age-at-onset modifier genes, FAN1 and RRM2B, for an influence on somatic instability of the expanded CAG repeat in Htt CAG knock-in mice. Fan1 knock-out increased somatic expansion of Htt CAG repeats, in the juvenile- and the adult-onset HD ranges, whereas knock-out of Rrm2b did not greatly alter somatic Htt CAG repeat instability. Simultaneous knock-out of Mlh1, the ortholog of a third HD age-at-onset modifier gene (MLH1), which suppresses somatic expansion of the Htt knock-in CAG repeat, blocked the Fan1 knock-out-induced acceleration of somatic CAG expansion. This genetic interaction indicates that functional MLH1 is required for the CAG repeat destabilizing effect of FAN1 loss. Thus, in HD, it is uncertain whether the RRM2B modifier effect on timing of onset may be due to a DNA instability mechanism. In contrast, the FAN1 modifier effects reveal that functional FAN1 acts to suppress somatic CAG repeat expansion, likely in genetic interaction with other DNA instability modifiers whose combined effects can hasten or delay onset and other CAG repeat length-driven phenotypes.

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What is the Pathogenic CAG Expansion Length in Huntington’s Disease?

Journal of Huntington s Disease ◽

10.3233/jhd-200445 ◽

2021 ◽

Vol 10 (1) ◽

pp. 175-202

Author(s):

Jasmine Donaldson ◽

Sophie Powell ◽

Nadia Rickards ◽

Peter Holmans ◽

Lesley Jones

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Confidence Intervals ◽

Age At Onset ◽

Cag Repeat ◽

Genetic Modifiers ◽

Tract Length ◽

Cag Expansion ◽

Age Dependent ◽

Step Mechanism

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.

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Differential Diagnosis of Chorea—HIV Infection Delays Diagnosis of Huntington’s Disease by Years

Brain Sciences ◽

10.3390/brainsci11060710 ◽

2021 ◽

Vol 11 (6) ◽

pp. 710

Author(s):

Jannis Achenbach ◽

Simon Faissner ◽

Carsten Saft

Keyword(s):

Hiv Infection ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Onset ◽

Diagnostic Delay ◽

Depression Scale ◽

Cag Repeat ◽

Psychiatric Disease ◽

Disease Manifestation ◽

Cross Sectional

Background: There is a broad range of potential differential diagnoses for chorea. Besides rare, inherited neurodegenerative diseases such as Huntington’s disease (HD) chorea can accompany basal ganglia disorders due to vasculitis or infections, e.g., with the human immunodeficiency virus (HIV). The clinical picture is complicated by the rare occurrence of HIV infection and HD. Methods: First, we present a case suffering simultaneously from HIV and HD (HIV/HD) focusing on clinical manifestation and disease onset. We investigated cross-sectional data regarding molecular genetic, motoric, cognitive, functional, and psychiatric disease manifestation of HIV/HD in comparison to motor-manifest HD patients without HIV infection (nonHIV/HD) in the largest cohort of HD patients worldwide using the registry study ENROLL-HD. Data were analyzed using ANCOVA analyses controlling for covariates of age and CAG repeat length between groups in IBM SPSS Statistics V.25. Results: The HD diagnosis in our case report was delayed by approximately nine years due to the false assumption that the HIV infection might have been the cause of chorea. Out of n = 21,116 participants in ENROLL-HD, we identified n = 10,125 motor-manifest HD patients. n = 23 male participants were classified as suffering from HIV infection as a comorbidity, compared to n = 4898 male non-HIV/HD patients. Except for age, with HIV/HD being significantly younger (p < 0.050), we observed no group differences regarding sociodemographic, genetic, educational, motoric, functional, and cognitive parameters. Male HIV/HD patients reported about a 5.3-year-earlier onset of HD symptoms noticed by themselves compared to non-HIV/HD (p < 0.050). Moreover, patients in the HIV/HD group had a longer diagnostic delay of 1.8 years between onset of symptoms and HD diagnosis and a longer time regarding assessment of first symptoms by the rater and judgement of the patient (all p < 0.050). Unexpectedly, HIV/HD patients showed less irritability in the Hospital Anxiety and Depression Scale (all p < 0.05). Conclusions: The HD diagnosis in HIV-infected male patients is secured with a diagnostic delay between first symptoms noticed by the patient and final diagnosis. Treating physicians therefore should be sensitized to think of potential alternative diagnoses in HIV-infected patients also afflicted by movement disorders, especially if there is evidence of subcortical atrophy and a history of hyperkinesia, even without a clear HD-family history. Those patients should be transferred for early genetic testing to avoid further unnecessary diagnostics and improve sociomedical care.

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The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

Journal of Huntington s Disease ◽

10.3233/jhd-200429 ◽

2021 ◽

Vol 10 (1) ◽

pp. 7-33

Author(s):

Darren G. Monckton

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Human Genetics ◽

Age At Onset ◽

Cag Repeat ◽

Model Systems ◽

Causative Mutation ◽

Inverse Association ◽

Independent Manner ◽

Dna Mismatch

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.

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