Parent-of-origin differences of mutant HTT CAG repeat instability in Huntington’s disease

doi:10.1016/j.ejmg.2011.04.002

European Journal of Medical Genetics

Volume 54, Issue 4, July–August 2011, Pages e413-e418

https://doi.org/10.1016/j.ejmg.2011.04.002 Get rights and content

Abstract

Background

Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). The CAG domain of mutant HTT is unstable upon intergenerational transmission, however, little is known about the underlying mechanisms.

Methods

From the HD archives of the Leiden University Medical Centre DNA samples from all parent-offspring pairs involving 36 CAG repeats or more were selected. To minimize procedural variability, CAG repeat lengths in both mutant and normal HTT were reassessed using the same standardized protocol, which resulted in the identification of 337 parent-offspring transmissions. The effects of both parental (mutant and normal CAG repeat size, age and gender) and offspring (gender and season of conception) characteristics on CAG repeat instability were assessed.

Results

Paternal transmissions were often associated with CAG repeat expansion, whereas maternal transmissions mainly resulted in CAG repeat contraction (mean change: +1.76 vs. −0.07, p < 0.001). Only in paternal transmissions larger mutant CAG repeat size was associated with a greater degree of CAG repeat expansion (β = 0.73; p < 0.001). Conversely, only in maternal transmissions larger CAG repeat size of the normal allele was associated with a greater degree of CAG repeat contraction (β = −0.07; p = 0.029). Parental age, offspring gender and season of conception were not related to CAG repeat instability.

Conclusion

Our findings suggest a slight maternal contraction bias as opposed to a paternal expansion bias of the mutant HTT CAG repeat during intergenerational transmission, which only in the maternal line is associated with normal HTT CAG repeat size.

Introduction

Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder characterized by motor disturbances, cognitive decline and behavioural problems [1]. The disease is caused by an expanded trinucleotide (CAG) repeat in the first exon of the HD gene (HTT) [2]. Normal HTT alleles contain 35 or less CAG repeats while mutant alleles are associated with 36 or more CAG repeats, although alleles with 36 to 39 repeats are considered to have reduced-penetrance. The length of the CAG repeat sequence in the mutant gene is inversely related to both age of onset, accounting for up to 73% of the variance [3], and disease progression [4], [5]. Except rare instances, CAG repeats in the normal range are stably inherited [6]. However, CAG repeats in the mutant range are generally unstable during intergenerational inheritance and can either contract or expand in up to 80% of all cases [7], [8], [9], [10].

The mechanisms underlying intergenerational CAG repeat instability are largely unknown. However, elucidating these mechanisms is of great importance as this could lead to better genetic counseling strategies, possible therapeutic interventions to counteract CAG repeat expansion and induce contraction, and a better understanding of the mechanisms that may also be responsible for somatic CAG repeat instability, which is associated with germ line repeat instability and is thought to be involved in HD pathogenesis [11], [12], [13], [14]. We recently demonstrated that the size of the CAG tract in the normal HTT allele also influences both age of onset and disease progression in HD patients [5]. However, it is still unclear whether normal CAG repeat size could also influence the intergenerational instability of the mutant CAG repeat tract. Therefore, in this study we aimed to identify factors that are associated with CAG repeat instability upon intergenerational transmission of the mutant allele, especially focusing on the role of the CAG tract size in the normal allele. In addition, as seasonal variations have been reported in germ cell quality of both men and women [15], [16], [17], we also sought to investigate whether day of birth of the offspring could influence CAG repeat instability.

Section snippets

Samples

From the archives of the department of Clinical Genetics of the Leiden University Medical Centre DNA samples from all parent-offspring pairs involving 36 CAG repeats or more in both generations were selected, concerning a total of 572 individual HD mutation carriers. To minimize procedural variability, CAG repeat lengths in both mutant and normal HTT were reassessed using the same standardized protocol and, in addition, all parent-offspring pairs were assessed in the same run. We excluded two

Results

In total, 337 transmissions of mutant HTT alleles from 190 different families were analyzed (Table 1). Mean ΔCAG was +1.76 in paternal transmissions and -0.07 in maternal transmissions (t = 5.12; p < 0.001). Moreover, paternal and maternal transmissions differed significantly for percent contractions versus expansions (χ² = 40.78; p < 0.001) (Fig. 1). As in one case the gender of the offspring was unknown, mutation inheritance split by the gender of both parent and offspring resulted in a total of 336

Discussion

The degree of intergenerational CAG repeat instability in our cohort of Dutch HD patients is comparable to that described in other HD populations [6], [7], [8], [9], [10]. In line with previous reports both the gender of the affected parent as well as the size of the CAG repeat mutation appeared to be major determinants of repeat instability [6], [7], [8], [9], [10]. However, age of the affected parent at the time of offspring’s birth was not associated with intergenerational CAG repeat

Acknowledgments

We would like to thank M. Losekoot, PhD, and E.K. Bijlsma, MD, PhD, for their critical comments and suggestions. N.A.Aziz was supported by The Netherlands Organization for Scientific Research (grant #017.003.098).

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The Cytosine–Adenine–Guanine (CAG) repeat mutation that causes Huntington's disease (HD) is characterized by its instability, or the tendency for the number of repeat units to increase or decrease. Such mutational properties have a bearing on many aspects of this disease, including the propensity to generate new mutations and relationships between genotype (repeat length) and clinical phenotypes. In this chapter, we describe the instability of the HD CAG repeat mutation upon transmission from one generation to the next and throughout a patient's life in somatic cells. We then discuss how insights from mouse models have helped us to understand factors that underlie repeat instability, and recent genome-wide association studies (GWAS) in HD patients that have highlighted a pivotal role for somatic repeat instability in driving disease. Finally, we address key outstanding questions to be addressed in future work that will deepen our understanding of the underlying biology of repeat instability and inform therapeutic strategies.
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Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?
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The CAG repeat domain size in HD features the parental sex-based expansion or contraction reflecting the gender bias that is associated with transmission (Kovtun et al., 2004). Studies of intergenerational instability in HD families have shown that the HTT CAG repeat is strongly biased toward expansions in transmission from fathers, while transmissions from mothers have a higher tendency to be stable or contract (Aziz et al., 2011; Neto et al., 2017). In a large Venezuelan cohort, a study investigated transmission instability for 184 fathers–offspring and 311 mothers– offspring pairs in the HD pedigree (Wheeler et al., 2007).
The impact of neurodegenerative disorders in humans has multiple consequences because of the progressive decline in cognitive and physical performances. These disorders have diverse manifestations and are influenced by genetic and lifestyle factors, concurrent health conditions as well as un-modifiable predisposing risk factors, including gender and advanced age. Accumulating evidence indicates a gender-dependent natural bias of neurodegenerative diseases, such as, Alzheimer's disease, Parkinson's disease, Huntington’s disease and multiple sclerosis, with the ratio of male to female prevalence as well as the severity of the disease differing significantly between the two sexes. This observation has recently garnered much attention and it is now being realized that understanding the sex as a biological variable in the etiology of the neurodegenerative diseases may advance the status of the pathophysiology and treatment strategies while improving the associated decline in cognitive and functional abilities. This review highlights the influence of gender in neurodegenerative disorders and further discusses the sex-specific pre-determined microenvironments that are critical in predisposing the individuals to such disorders.
Risk factors for the onset and progression of Huntington disease
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Citation Excerpt :
Although one article (Aziz et al., 2011) reported a non-significant trend for an inverse association between normal CAG repeat size of the affected parent and the intergenerational CAG repeat length changes (p = 0.098), another article (Kremer et al., 1995) found the CAG size on the normal chromosome of the affected parent(r = 0.012; P = 0.85) had no influence on CAG instability of the affected chromosome. Two articles (Kremer et al., 1995; Aziz et al., 2011), found the CAG size of the normal chromosome of the offspring had no influence on CAG instability of the affected chromosome. Using birth order and age of the affected parent at offspring’s conception or birth, five studies (Aziz et al., 2011; Wheeler et al., 2007; Norremolle et al., 1995; Ramos et al., 2012; Telenius et al., 1993) consistently showed there was no association between the parental age and the intergenerational CAG repeat changes.
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by chorea, behavioural and psychiatric manifestations, and dementia, caused by a CAG triplet repeat expansion in the huntingtin gene. Systematic review of the literature was conducted to determine the risk factors for the onset and progression of HD. Multiple databases were searched, using terms specific to Huntington disease and to studies of aetiology, risk, prevention and genetics, limited to studies on human subjects published in English or French between 1950 and 2010. Two reviewers independently screened the abstracts and identified potentially relevant articles for full-text review using predetermined inclusion criteria. Three major categories of risk factors for onset of HD were identified: CAG repeat length in the huntingtin gene, CAG instability, and genetic modifiers. Of these, CAG repeat length in the huntingtin gene is the most important risk factor. For the progression of HD: genetic, demographic, past medical/clinical and environmental risk factors have been studied. Of these factors, genetic factors appear to play the most important role in the progression of HD. Among the potential risk factors, CAG repeat length in the mutant allele was found to be a relatively consistent and significant risk factor for the progression of HD, especially in motor, cognitive, and other neurological symptom deterioration. In addition, there were many consistent results in the literature indicating that a higher number of CAG repeats was associated with shorter survival, faster institutionalization, and earlier percutaneous endoscopic gastrostomy.
Huntington's disease: Actual data for psychiatric disorder therapeutic
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Pour ce faire, nous illustrerons, dans un premier temps, la prise en charge effectuée par nos équipes sur deux patientes atteintes de cette pathologie. Puis, nous effectuerons une revue de la littérature relative à la prise en charge psychiatrique de la pathologie.
Les symptômes psychiatriques les plus retrouvés dans cette pathologie sont l’anxiété, la dépression, l’irritabilité, l’agressivité ainsi que les états psychotiques. L’utilisation des inhibiteurs sélectifs de la recapture de la sérotonine et des inhibiteurs sélectifs de la sérotonine et de la noradrénaline pour les troubles thymiques en est la référence. L’électroconvulsivothérapie et les thymorégulateurs présentent des résultats similaires à ceux obtenus dans les troubles thymiques sans pathologie neurodégénérative associée. Concernant les neuroleptiques, la préférence ira aux antipsychotiques de seconde génération par la moindre présence des effets secondaires.
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Huntington's disease is a neurodegenerative genetic, autosomal dominant disease. George Huntington describes this trouble in 1872. In 1993, scientist founded mutation on IT15 gene on 4th chromosome. Prevalence in France is 1/10 000 without sex predominance or race. The main symptoms are: choreic movements, axial impairment, psychiatric disorders and the presence of cognitive impairment. The diagnostic is clinic, genetic and radiologic. Despite the absence of curative treatment, symptomatic care supports deficit symptoms of the pathology, thus improves the quality of life of patients. In the context of a comprehensive and optimal therapy, health professionals provide recommendations for guidelines like Huntington's disease national reference center in August 2015. We will define diagnostic and clinical aspects of Huntington's disease, and then we will focus our analysis on the psychiatric aspect.
First, we will illustrate management provided by our teams. Patient A had positive diagnostic of Huntington's disease and personal psychiatric antecedent of depression. She was hospitalized in neurological unit for a panic attack in August 2015. They give tetrabenazine and to prevent depressive effect we prescribed antidepressant first (serotonin–norepinephrine reuptake inhibitor), then antipsychotic (risperidone, then haloperidol) and benzodiazepine. Patient B had Huntington's disease in family and personal diagnostic of Huntington's disease and personal psychiatric antecedent of depression. She was admitted in psychiatric unit for psychotic symptom. She received antipsychotic (risperidone) and antidepressant (venlafaxine) with benzodiazepine. Both of them had clinical improvement. Patient A, went to reeducation care, patient B went home with nurse. When we analyzed literature on the psychiatric therapeutic in Huntington's disease with review, we found that apathy is the most psychiatric symptom in Huntington's disease (50–80% Inserm). Benzodiazepine had good result for anxiety. We must search and treat psychiatric disorder like depression and mood disorder. Irritability and anxiety are symptoms of mood disorder and can be treated with antidepressive and mood stabilizer. Suicide is an emergency because of the mortality rate. The guideline is the same of suicide in psychiatric emergency. Antipsychotics are not avoided and used for choreic and psychotic symptoms (delirium, hallucination…) but second generation antipsychotics are generally preferable because of the lesser presence of adverse event.
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The implementation of classical specific therapeutic in psychiatry improves these symptoms and optimizes the quality of life for our patients. A comprehensive and multidisciplinary support involving medical and paramedical rehabilitation is a necessity to take into account.
Absence of MutSβ leads to the formation of slipped-DNA for CTG/CAG contractions at primate replication forks
2016, DNA Repair
Citation Excerpt :
The ongoing somatic expansions of trinucleotide repeats are thought to contribute to disease progression and severity. Notably, individuals with smaller expansion sizes have later age-of-onset, less severe disease and slower progression [1–17]. Due to differences in gene expression profiles between tissues [41,99], or differences in replication origin usage [27], certain tissues could have a greater propensity to form slipped-DNA structures, which could alter trinucleotide repeat instability.
Typically disease-causing CAG/CTG repeats expand, but rare affected families can display high levels of contraction of the expanded repeat amongst offspring. Understanding instability is important since arresting expansions or enhancing contractions could be clinically beneficial. The MutSβ mismatch repair complex is required for CAG/CTG expansions in mice and patients. Oddly, by unknown mechanisms MutSβ-deficient mice incur contractions instead of expansions. Replication using CTG or CAG as the lagging strand template is known to cause contractions or expansions respectively; however, the interplay between replication and repair leading to this instability remains unclear. Towards understanding how repeat contractions may arise, we performed in vitro SV40-mediated replication of repeat-containing plasmids in the presence or absence of mismatch repair. Specifically, we separated repair from replication: Replication mediated by MutSβ- and MutSα-deficient human cells or cell extracts produced slipped-DNA heteroduplexes in the contraction- but not expansion-biased replication direction. Replication in the presence of MutSβ disfavoured the retention of replication products harbouring slipped-DNA heteroduplexes. Post-replication repair of slipped-DNAs by MutSβ-proficient extracts eliminated slipped-DNAs. Thus, a MutSβ-deficiency likely enhances repeat contractions because MutSβ protects against contractions by repairing template strand slip-outs. Replication deficient in LigaseI or PCNA-interaction mutant LigaseI revealed slipped-DNA formation at lagging strands. Our results reveal that distinct mechanisms lead to expansions or contractions and support inhibition of MutSβ as a therapeutic strategy to enhance the contraction of expanded repeats.

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Original articleParent-of-origin differences of mutant HTT CAG repeat instability in Huntington’s disease

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Samples

Results

Discussion

Acknowledgments

Mol. Cell Probes

Trends Mol. Med.

Am. J. Hum. Genet.

J. Biol. Chem.

Huntington’s Disease

A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes

Cell

A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length

Clin. Genet.

Weight loss in Huntington disease increases with higher CAG repeat number

Neurology

Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease

Neurology

Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes

Am. J. Hum. Genet.

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

J. Med. Genet.

Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm

Nat. Genet.

Mitotic stability and meiotic variability of the (CAG)n repeat in the Huntington disease gene

Hum. Mol. Genet.

Factors associated with HD CAG repeat instability in Huntington disease

J. Med. Genet.

Intergenerational CAG repeat instability is highly heritable in Huntington’s disease

J. Med. Genet.

HA novel approach to investigate tissue-specific trinucleotide repeat instability

BMC Syst. Biol.

Somatic mosaicism in sperm is associated with intergenerational (CAG)n changes in Huntington disease

Hum. Mol. Genet.

Somatic expansion of the Huntington’s disease CAG repeat in the brain is associated with an earlier age of disease onset

Hum. Mol. Genet.

Original article
Parent-of-origin differences of mutant HTT CAG repeat instability in Huntington’s disease