Huntington’s disease onset is determined by length of uninterrupted CAG, not encoded polyglutamine, and is modified by DNA maintenance mechanisms

SUMMARYThe effects of variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from huntingtin’s polyglutamine segment, dictates the rate at which HD develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally-occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question a fundamental premise of the “polyglutamine disorders”.

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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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Dystonia in Patients with Spinocerebellar Ataxia 3 - Machado-Joseph disease: An Underestimated Diagnosis?

The Open Neurology Journal ◽

10.2174/1874205x01812010041 ◽

2018 ◽

Vol 12 (1) ◽

pp. 41-49 ◽

Cited By ~ 2

Author(s):

Ligia Maria Perrucci Catai ◽

Carlos Henrique Ferreira Camargo ◽

Adriana Moro ◽

Gustavo Ribas ◽

Salmo Raskin ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Movement Disorders ◽

Disease Onset ◽

Cag Repeat ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 3 ◽

Generalized Dystonia ◽

Machado Joseph Disease ◽

Sca3 Patient ◽

Type 3

Background:Spinocerebellar Ataxia type 3 (SCA3) or Machado-Joseph Disease (MJD) is characterized by cerebellar, central and peripheral symptoms, including movement disorders. Dystonia can be classified as hereditary and neurodegenerative when present in SCA3.Objective:The objective of this study was to evaluate the dystonia characteristics in patients with MJD.Method:We identified all SCA3 patients with dystonia from the SCA3 HC-UFPR database, between December 2015 and December 2016.Their medical records were reviewed to verify the diagnosis of dystonia and obtain demographic and clinical data. Standardized evaluation was carried out through the classification of Movement Disorders Society of 2013 and Burke Fahn-Marsden scale (BFM).Results:Amongst the presenting some common characteristics, 381 patients with SCA3, 14 (3.7%) subjects presented dystonia: 5 blepharospasm, 1 cervical dystonia, 3 oromandibular, 3 multifocal and 2 generalized dystonia. Regarding dystonia's subtypes, 71.4% had SCA3 subtype I and 28.6% SCA3 subtype II. The average age of the disease onset was 40±10.7 years; the SCA3 disease duration was 11.86± 6.13 years; the CAG repeat lengths ranged from 75 to 78, and the BFM scores ranged from 1.0 to 40. There was no correlation between the dystonia severity and CAG repeat lengths or the SCA3 clinical evolution.Conclusion:Dystonia in SCA3 is frequent and displays highly variable clinical profiles and severity grades. Dystonia is therefore a present symptom in SCA3, which may precede the SCA3 classic symptoms. Dystonia diagnosis is yet to be properly recognized within SCA3 patient.

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Predicting Disease Onset from Mutation Status Using Proband and Relative Data with Applications to Huntington's Disease

Journal of Probability and Statistics ◽

10.1155/2012/375935 ◽

2012 ◽

Vol 2012 ◽

pp. 1-19 ◽

Cited By ~ 3

Author(s):

Tianle Chen ◽

Yuanjia Wang ◽

Yanyuan Ma ◽

Karen Marder ◽

Douglas R. Langbehn

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Family Member ◽

Disease Onset ◽

Repeat Length ◽

Cag Repeat ◽

Cag Repeats ◽

Observational Research ◽

Accurate Estimation ◽

Combined Data

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of CAG repeats in the IT15 gene. The age-at-onset (AAO) of HD is inversely related to the CAG repeat length and the minimum length thought to cause HD is 36. Accurate estimation of the AAO distribution based on CAG repeat length is important for genetic counseling and the design of clinical trials. In the Cooperative Huntington's Observational Research Trial (COHORT) study, the CAG repeat length is known for the proband participants. However, whether a family member shares the huntingtin gene status (CAG expanded or not) with the proband is unknown. In this work, we use the expectation-maximization (EM) algorithm to handle the missing huntingtin gene information in first-degree family members in COHORT, assuming that a family member has the same CAG length as the proband if the family member carries a huntingtin gene mutation. We perform simulation studies to examine performance of the proposed method and apply the methods to analyze COHORT proband and family combined data. Our analyses reveal that the estimated cumulative risk of HD symptom onset obtained from the combined data is slightly lower than the risk estimated from the proband data alone.

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A Patient-Derived Cellular Model for Huntington’s Disease Reveals Phenotypes at Clinically Relevant CAG Lengths

10.1101/291575 ◽

2018 ◽

Author(s):

Claudia Lin-Kar Hung ◽

Tamara Maiuri ◽

Laura Erin Bowie ◽

Ryan Gotesman ◽

Susie Son ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Cell Lines ◽

Disease Onset ◽

Cag Repeat ◽

Dna Repeats ◽

Cellular Model ◽

Human Telomerase Reverse Transcriptase ◽

Huntingtin Protein ◽

Transformed Cell Lines

ABSTRACTThe huntingtin protein participates in several cellular processes that are disrupted when the polyglutamine tract is expanded beyond a threshold of 37 CAG DNA repeats in Huntington’s disease (HD). Cellular biology approaches to understand these functional disruptions in HD have primarily focused on cell lines with synthetically long CAG length alleles that clinically represent outliers in this disease and a more severe form of HD that lacks age-onset. Patient-derived fibroblasts are limited to a finite number of passages before succumbing to cellular senescence. We used human telomerase reverse transcriptase (hTERT) to immortalize fibroblasts taken from individuals of varying age, sex, disease onset and CAG repeat length, which we have termed TruHD cells. TruHD cells display classic HD phenotypes of altered morphology, size and growth rate, increased sensitivity to oxidative stress, aberrant ADP/ATP ratios and hypophosphorylated huntingtin protein. We additionally observed dysregulated ROS-dependent huntingtin localization to nuclear speckles in HD cells. We report the generation and characterization of a human, clinically relevant cellular model for investigating disease mechanisms in HD at the single cell level, which, unlike transformed cell lines, maintains TP53 function critical for huntingtin transcriptional regulation and genomic integrity.

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Inhibition of Proteasomal Activity Causes Inclusion Formation in Neuronal and Non-Neuronal Cells Overexpressing Parkin

Molecular Biology of the Cell ◽

10.1091/mbc.e03-02-0078 ◽

2003 ◽

Vol 14 (11) ◽

pp. 4541-4556 ◽

Cited By ~ 83

Author(s):

Helen C. Ardley ◽

Gina B. Scott ◽

Stephen A. Rose ◽

Nancy G. S. Tan ◽

Alexander F. Markham ◽

...

Keyword(s):

Autosomal Recessive ◽

Disease Onset ◽

Lewy Bodies ◽

26S Proteasome ◽

Contributory Factor ◽

Proteasomal Activity ◽

Polyglutamine Disorders ◽

Autosomal Recessive Juvenile Parkinsonism ◽

Juvenile Parkinsonism ◽

Sporadic Disease

Association between protein inclusions and neurodegenerative diseases, including Parkinson's and Alzheimer's diseases, and polyglutamine disorders, has been widely documented. Although ubiquitin is conjugated to many of these aggregated proteins, the 26S proteasome does not efficiently degrade them. Mutations in the ubiquitin-protein ligase Parkin are associated with autosomal recessive juvenile Parkinsonism. Although Parkin-positive inclusions are not detected in brains of autosomal recessive juvenile Parkinsonism patients, Parkin is found in Lewy bodies in sporadic disease. This suggests that loss of Parkin ligase activity via mutation, or sequestration to Lewy bodies, is a contributory factor to sporadic disease onset. We now demonstrate that decreased proteasomal activity causes formation of large, noncytotoxic inclusions within the cytoplasm of both neuronal and nonneuronal cells overexpressing Parkin. This is not a general phenomenon as there is an absence of similar inclusions when HHARI, a structural homolog of Parkin, is overexpressed. The inclusions colocalize with ubiquitin and with proteasomes. Furthermore, Parkin inclusions colocalize with γ-tubulin, acetylated α-tubulin, and cause redistribution of vimentin, suggesting aggresome-like properties. Our data imply that lower proteasomal activity, previously observed in brain tissue of Parkinson's disease patients, leads to Parkin accumulation and a concomitant reduction in ligase activity, thereby promoting Lewy body formation.

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CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders

RNA Biology ◽

10.4161/rna.8.4.15397 ◽

2011 ◽

Vol 8 (4) ◽

pp. 565-571 ◽

Cited By ~ 24

Author(s):

Marzena Wojciechowska ◽

Wlodzimierz J. Krzyzosiak

Keyword(s):

Cag Repeat ◽

Toxic Agent ◽

Polyglutamine Disorders

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Hepatitis C Virus Induces Regulatory T Cells by Naturally Occurring Viral Variants to Suppress T Cell Responses

Clinical and Developmental Immunology ◽

10.1155/2011/806061 ◽

2011 ◽

Vol 2011 ◽

pp. 1-15 ◽

Cited By ~ 17

Author(s):

Matthew F. Cusick ◽

Jennifer J. Schiller ◽

Joan C. Gill ◽

David D. Eckels

Keyword(s):

T Cells ◽

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Regulatory T Cell ◽

Cell Response ◽

T Cell Response ◽

Cell Responses ◽

Naturally Occurring ◽

Specific Manner

Regulatory T cell markers are increased in chronically infected individuals with the hepatitis C virus (HCV), but to date, the induction and maintenance of Tregs in HCV infection has not been clearly defined. In this paper, we demonstrate that naturally occurring viral variants suppress T cell responses to cognate NS3358-375in an antigen-specific manner. Of four archetypal variants, S370P induced regulatory T cell markers in comparison to NS3358-375-stimulated CD4 T cells. Further, the addition of variant-specific CD4 T cells back into a polyclonal culture in a dose-dependent manner inhibited the T cell response. These results suggest that HCV is able to induce antigen-specific regulatory T cells to suppress the antiviral T cell response in an antigen-specific manner, thus contributing to a niche within the host that could be conducive to HCV persistence.

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FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders

Journal of Huntington s Disease ◽

10.3233/jhd-200448 ◽

2021 ◽

Vol 10 (1) ◽

pp. 95-122

Author(s):

Amit L. Deshmukh ◽

Antonio Porro ◽

Mohiuddin Mohiuddin ◽

Stella Lanni ◽

Gagan B. Panigrahi ◽

...

Keyword(s):

Dna Repair ◽

Age Of Onset ◽

Disease Onset ◽

Repeat Expansion ◽

Cag Repeat ◽

Common Mechanism ◽

Clinical Effects ◽

Single Nucleotide Variants ◽

Cgg Repeat ◽

Repeat Expansions

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.

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Association Analysis of Chromosome X to Identify Genetic Modifiers of Huntington’s Disease

Journal of Huntington s Disease ◽

10.3233/jhd-210485 ◽

2021 ◽

pp. 1-9

Author(s):

Eun Pyo Hong ◽

Michael J. Chao ◽

Thomas Massey ◽

Branduff McAllister ◽

Sergey Lobanov ◽

...

Keyword(s):

Dna Repair ◽

Huntington's Disease ◽

Association Analysis ◽

X Chromosome ◽

Age At Onset ◽

Cag Repeat ◽

Chromosome X ◽

Repeat Instability ◽

Genome Wide ◽

Dna Maintenance

Background: Huntington’s disease (HD) is caused by an expanded (>35) CAG trinucleotide repeat in huntingtin (HTT). Age-at-onset of motor symptoms is inversely correlated with the size of the inherited CAG repeat, which expands further in brain regions due to somatic repeat instability. Our recent genetic investigation focusing on autosomal SNPs revealed that age-at-onset is also influenced by genetic variation at many loci, the majority of which encode genes involved in DNA maintenance/repair processes and repeat instability. Objective: We performed a complementary association analysis to determine whether variants in the X chromosome modify HD. Methods: We imputed SNPs on chromosome X for ∼9,000 HD subjects of European ancestry and performed an X chromosome-wide association study (XWAS) to test for association with age-at-onset corrected for inherited CAG repeat length. Results: In a mixed effects model XWAS analysis of all subjects (males and females), assuming random X-inactivation in females, no genome-wide significant onset modification signal was found. However, suggestive significant association signals were detected at Xq12 (top SNP, rs59098970; p-value, 1.4E-6), near moesin (MSN), in a region devoid of DNA maintenance genes. Additional suggestive signals not involving DNA repair genes were observed in male- and female-only analyses at other locations. Conclusion: Although not genome-wide significant, potentially due to small effect size compared to the power of the current study, our data leave open the possibility of modification of HD by a non-DNA repair process. Our XWAS results are publicly available at the updated GEM EURO 9K website hosted at https://www.hdinhd.org/ for browsing, pathway analysis, and data download.

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