Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease

Wright, Galen E.B.; Caron, Nicholas S.; Ng, Bernard; Casal, Lorenzo; Xu, Xiaohong; Ooi, Jolene; Pouladi, Mahmoud A.; Mostafavi, Sara; Ross, Colin J.D.; Hayden, Michael R.

doi:10.1101/699033

Cited by 3 publications

(8 citation statements)

References 66 publications

(84 reference statements)

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“…In contrast, again consistent with the results from model systems, SNPs associated with decreased MSH3 expression were associated with later disease onset, whilst SNPs associated with increased expression resulted in earlier ages of onset [22,136]. TWAS has also shown a correlation between increased PMS2 expression and a later age at disease onset [23] which would be consistent with the protective effect of PMS2 in some mouse models. The situation is less clear for PMS1 where TWAS showed a variable effect, with an increase in cortex PMS1 expression being associated with a later HD onset [22], whilst data from other tissue sources suggest the opposite (P. Holmans, personal communication).…”

Section: The Relevance Of These Models To Somatic Expansions In Hd Pasupporting

confidence: 82%

“…In the case of FAN1, SNPs associated with earlier HD onset include missense variants within or near FAN1's DNA-binding domain, consequently reducing its DNA-binding activity and capacity to rescue mitomycin C-induced cytotoxicity [135]. In addition, SNPs associated with later HD onset are associated with increased FAN1 expression in various brain regions [23,135]. This is consistent with FAN1 activity protecting against expansions in humans, as in HD and FXD mice [58,119,120].…”

Section: The Relevance Of These Models To Somatic Expansions In Hd Pamentioning

confidence: 52%

“…This includes the fact that larger somatic expansions in HD postmortem brain are associated with an earlier disease onset [20], and the observation that HD patients with higher levels of somatic expansion measured in blood have worse HD outcomes [21]. Furthermore, individuals with pure CAG repeat tracts have an earlier age at onset than individuals with CAA interruptions at the 3 end of the repeat tract [21][22][23]. While such interruptions do not change the number of glutamines in the PolyQ tract, they result in a reduction in somatic expansion [23].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, individuals with pure CAG repeat tracts have an earlier age at onset than individuals with CAA interruptions at the 3 end of the repeat tract [21][22][23]. While such interruptions do not change the number of glutamines in the PolyQ tract, they result in a reduction in somatic expansion [23]. This suggests that the rate of further repeat expansion during an individual's lifetime is an important contributor to HD onset.…”

Section: Introductionmentioning

confidence: 99%

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Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders: Implications for the Mechanism of Somatic Expansion in Huntington’s Disease

Zhao

Kumari

Miller

et al. 2021

JHD

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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.

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Section: The Relevance Of These Models To Somatic Expansions In Hd Pasupporting

confidence: 82%

Section: The Relevance Of These Models To Somatic Expansions In Hd Pamentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders: Implications for the Mechanism of Somatic Expansion in Huntington’s Disease

Zhao

Kumari

Miller

et al. 2021

JHD

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show abstract

“…The tagSNPs of FAN1 associated with modifying HD onset may be associated with altered expression of FAN1 mRNA, whereby increased or decreased FAN1 levels are beneficial or detrimental, respectively [12,14,15,139]. Both expression quantitative trait loci (eQTL) and transcriptome-wide association studies [140] suggest that the SNPs are associated with changes of FAN1 mRNA expression levels in specific brain regions but have no apparent effect on the expression of proximal genes, including MTMR10 or TRPM1 [12,141].…”

Section: Modifiers May Alter Expression Levels Of Fan1 Mrnamentioning

confidence: 99%

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

Deshmukh

Porro

Mohiuddin

et al. 2021

JHD

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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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Huntington disease update: new insights into the role of repeat instability in disease pathogenesis

Arning

Nguyen

2021

Medizinische Genetik

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The causative mutation for Huntington disease (HD), an expanded trinucleotide repeat sequence in the first exon of the huntingtin gene (HTT) is naturally polymorphic and inevitably associated with disease symptoms above 39 CAG repeats. Although symptomatic medical therapies for HD can improve the motor and non-motor symptoms for affected patients, these drugs do not stop the ongoing neurodegeneration and progression of the disease, which results in severe motor and cognitive disability and death. To date, there is still an urgent need for the development of effective disease‐modifying therapies to slow or even stop the progression of HD. The increasing ability to intervene directly at the roots of the disease, namely HTT transcription and translation of its mRNA, makes it necessary to understand the pathogenesis of HD as precisely as possible. In addition to the long-postulated toxicity of the polyglutamine-expanded mutant HTT protein, there is increasing evidence that the CAG repeat-containing RNA might also be directly involved in toxicity. Recent studies have identified cis- (DNA repair genes) and trans- (loss/duplication of CAA interruption) acting variants as major modifiers of age at onset (AO) and disease progression. More and more extensive data indicate that somatic instability functions as a driver for AO as well as disease progression and severity, not only in HD but also in other polyglutamine diseases. Thus, somatic expansions of repetitive DNA sequences may be essential to promote respective repeat lengths to reach a threshold leading to the overt neurodegenerative symptoms of trinucleotide diseases. These findings support somatic expansion as a potential therapeutic target in HD and related repeat expansion disorders.

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Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease

Cited by 3 publications

References 66 publications

Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders: Implications for the Mechanism of Somatic Expansion in Huntington’s Disease

Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders: Implications for the Mechanism of Somatic Expansion in Huntington’s Disease

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

Huntington disease update: new insights into the role of repeat instability in disease pathogenesis

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