HD mouse models of CAG repeat instability.
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder whose characterstics were first described by George Huntington in 1872. Several decades later, in 1993, the mutation behind this disease was found to be an unstable expanded CAG repeat within exon 1 of the HTT gene localized on the short arm of chromosome 4. The majority of HD patients carry more than 40 CAG repeats, which become unstable and usually increase in size in successive generations and in tissues. In order to dissect the molecular mechanisms underlying CAG repeat instability, several HD mouse models have been created in the 1990s. Significant data have revealed that the absence of proteins from the mismatch repair (MMR) or the base and nucleotide excision repair decreased the pathogenic expansion‐biased somatic mosaicism and/or intergenerational expansions. Some polymorphic variants of MMR genes have also been associated with reduced somatic expansions. Since expansion‐biased somatic mosaicism likely contributes to disease manifestations, these results suggest that genetic modifiers of instability may also affect disease severity. In this chapter, we provide an overview of the data recently published about DNA instability; the roles of genetic modifiers of trinucleotide repeat dynamics in mouse models; and the possible therapeutic interventions.
- Huntington disease
- DNA instability
- mouse models
- genetic modifiers
Expansions of repetitive DNA sequences, including trinucleotide repeats, are associated with a large number of neurological and neuromuscular disorders, such as fragile X syndrome, myotonic dystrophy type 1 and Huntington's disease (HD) [1, 2]. In the healthy population, the triplet repeat tract size varies between 5 and 30 repeats and is stable. In HD patients, the pathogenic allele contains more than 40 repeats and becomes highly unstable and usually increases in size in successive generations (intergenerational instability) and in somatic tissues (somatic instability). Longer expanded alleles are associated with more severe forms of disease and result in a decreasing age of onset from one generation to the next [1, 3, 4]. Among trinucleotide repeat disorders, HD disease is the fourth reported.
1.1. Clinical picture of HD
Huntington's disease is an autosomal dominant neurodegenerative disorder with a worldwide incidence varying from 0.1 to 10 per 100,000 people depending on the country. The estimation of prevalence varies according to haplogroups studied: it is estimated from 2 to 7 per 100,000 in the Caucasians and only 0.1–1 per 100,000 in Asians and Africans [5, 6]. Adult‐onset Huntington disease is the most common form of HD and usually presents in early middle life. HD symptoms include uncontrolled movements such as chorea, progressive cognitive impairment and neuropsychiatric manifestations. The rare early‐onset form of the disease also called juvenile form presents more severe symptoms with rigidity and motor dysfunctions . HD symptoms and severity vary greatly among family patients and between juvenile and adult onset forms. Currently, no treatment is suitable to stop or reverse any form of HD.
1.2. Genetic of HD
HD is caused by an unstable expanded CAG repeat within exon 1 of the
1.2.1. Intergenerational instability
The frequencies of expanded, unchanged and contracted alleles have been investigated by directly comparing the length of the repeat tract in each parent with that is observed in their progeny to estimate the degree of intergenerational instability in each set of HD cohort. Small normal alleles with CAG repeat size ranging from 10 to 28 CAG are genetically stable with germline mutation rates <1% per generation . However, the mutation frequency rises dramatically with the increasing size of the allele. Indeed, a CAG repeat size change on expanded allele in the range of 36–49 repeats occurs in >70% of transmissions from affected parents to HD children. A similar rate of expansion was found between multiethnic cohorts [13–19]. In the two largest cohorts (>250 parent‐offspring pairs), the frequency of expansions was estimated to be 52.1% in a multiethnic HD population and 67.3% in the Dutch cohort, whereas only 18.1% and 25.2% contractions were observed, respectively [13, 18]. For individuals carrying more than 49 CAG repeats, the mutation rates go up to >95% per generation [14, 20]. In all cases, the frequency of expansions always exceeds the frequency of contractions in HD populations. The instability of the CAG repeat between generations depends on the sex of the transmitting parent and the length of the repeat itself. Studies of the two cohorts of HD individuals with the mean size of ∼43 CAG repeats have shown that 61–68% of paternal transmissions resulted in expansions, whereas the majority (>60%) of maternal transmissions resulted in contractions or CAG stabilization [13, 18]. The largest expansions, associated with the juvenile form of HD, are almost observed in male transmissions and are influenced by the CAG repeat length of the transmitting parent . The largest HD cohort study (337 transmissions) has shown that the age of the transmitting parents and the sex of offspring do not affect the intergenerational instability, suggesting that the gender of affected parents is the major modifier of intergenerational instability . Repeat size variability has been investigated in spermatogonia, postmitotic spermatid and matura spermatozoa collected by laser capture microdissection of testis from two HD patients in order to determine the timing of repeat instability. Interestingly, CAG repeat expansions were already present before the end of the first meiotic division and the frequency continues to increase in postmeiotic cell population suggesting that the primary source of instability occurs in spermatogonia .
1.2.2. Somatic instability
Several studies have reported that the expanded CAG repeat allele is also unstable in somatic tissues and increases in length over time [22–25]. Somatic CAG repeat size variation was analyzed by bulk PCR in each tissue whereas the degree of somatic mosaicism was quantified by a more sensitive PCR‐based approach called Small‐Pool PCR . This method allows to accurately assess the variation of CAG repeat length of each HD expanded allele in tissues, using successive DNA dilutions in order to amplify few template molecules per reaction (Figure 2A). The dynamics of somatic CAG repeat instability varies between and within tissues with the highest instability observed in the striatum and cortex, two tissues that show the most pronounced neuropathological abnormalities [22, 23, 25]. In a large Venezuelan HD cohort, a positive correlation was reported between the size of progenitor alleles (inherited alleles) and the expansion‐biased somatic mosaicism in buccal cells from individuals at the same age. This observation suggests that the size of the inherited CAG repeat is an important modulator of somatic instability . Furthermore, it has been reported that CAG repeat expansion length in the cortex is associated with an earlier age of disease onset suggesting that somatic instability is a significant predictor of the age of onset . Interestingly, somatic instability was not observed in two fetuses at 12–13 weeks suggesting that the somatic expansion event occurs later in the stages of fetal development or from birth throughout the patient's life .
Together, these data have clearly demonstrated the contribution of the sex of the transmitting parent and the inherited length of the CAG repeat in the dynamics of intergenerational and somatic instability in HD patients. Moreover, both germline and somatic mosaicism level seems to be linked to the disease onset and to the progression of HD symptoms. Thus, aiming at decreasing the size of expanded alleles or the level of somatic mosaicism would be an attractive therapeutic strategy. In the majority of analyses, the degree of expansion length variability between tissues and individuals cannot be explained only by the age, sex of the transmitting parent and the progenitor allele size, therefore implying that genetic factors might influence either germline or somatic instability. In 2012, the study of a large Portuguese HD cohort has reported some HD families with extreme repeat length changes from parents to offspring suggesting the existence of modifiers that may be heritable . Hence, the understanding of CAG repeat instability is crucial to improve the therapeutic possibilities. Analyses of genetic modifiers of instability and dissection of mechanisms involved in this process are compromised by the limited accessibility of human samples and clinical information. Then, knockout, transgenic and knock‐in HD mouse models have been generated to dissect the molecular mechanisms of instability and the pathogenesis of HD disease [30, 31].
2. Mouse models of CAG repeat instability
The dynamics of expanded CAG repeat has already been analyzed in different simple organism strains such as bacteria and yeast by inserting a plasmid with a pathogenic CAG repeat. Analyses in
|Mouse models||Genetic background||Transgene||CAG repeat length||Mutation
instability (CAG length variation)
|[32, 45, 46, 51, 52]|
|CAG repeat locus||18||None||None|||
|[24, 56, 57]|
|109||73%||[24, 56, 57, 58]|
|[25, 33, 38, 39]|
BACHD mouse model was established by the introduction of a full‐length human
2.1. R6 transgenic mouse lines
The first successful HD transgenic mouse model was created in 1996 and called R6 lines of HD transgenic mice . These mice were obtained by random integration of a short 5’ fragment of human
To evaluate intergenerational CAG repeat lengths, fluorescent PCR using DNA from tail biopsy at 3 weeks of age was performed in R6/0, R6/1, R6/2 parents and offspring. The comparison of CAG repeat lengths between parents and their progeny is limited in R6/5 mice due to the integration of multiple transgene copies in the genome of this line. Compared to R6/1 and R6/2, R6/0 mice do not show any evidence of CAG repeat instability and any transgene expression. As observed in HD patients, R6/1 and R6/2 mice mimic intergenerational instability biased toward expansions across paternal transmissions and toward contractions during R6/1 maternal transmissions (R6/2 female mice are infertile) with a mutation rate from 65 to 84% [45, 46]. Interestingly, the CAG repeat size changes depend on the gender of R6/1 embryos with a high expansion rate in males and high contraction rate in females from the same fathers suggesting that offspring sex‐dependent genes modulate intergenerational instability in R6/1 mice . In R6/2 mice, the size of transmitted CAG expansion increases with the age of transmitting males . A selective R6/2 breeding enabled to obtain numerous R6/2 colonies with inheriting CAG repeat ranging from ∼110 to 450 [47–49]. The size of CAG repeat is positively correlated with the severity of symptoms up to ∼160 CAG repeats . Surprisingly, some neurological symptoms and a lifespan are greatly ameliorated in R6/2 mice carrying more than 200 CAG repeat expansions [47–49]. These unexpected results can be explained by transgene expression decrease observed in these mice . A spontaneous contraction from 116 to ∼89 CAG repeat was described in R6/1 mice . These mice showed a decreased age of onset and a HD phenotypic improvement compared to R6/1 mice with 116 CAG repeat supporting the relationship between the CAG repeat size and the progression of symptoms.
Somatic instability of the CAG repeat tracts has been also reported in R6 lines carrying CAG repeat expansions excepted for the R6/0 line . R6/1 and R6/2 recreated expansion‐biased, age‐dependent and tissue‐specific somatic mosaicism as observed in HD patients [38, 51, 52]. Liver and striatum have shown the highest levels of instability biased toward expansions compared to other tissues that have shown low or no instability in both lines. Two distinct modes of somatic expansion have been described in tissues from R6/1 mice. Striatum and cortex have shown a periodic expansion, whereas the other tissues reproduce a short continuous expansion overtime suggesting different mechanisms of instability in these tissues . Large spontaneous expansions (>200 CAG) have been described in striatum and cortex from R6/2 mice  consistent with the observations done in brain from HD patients [25, 43]. In R6/2 mice, the somatic mosaicism is correlated with the transmitted CAG repeat size but the somatic variation is not linear, particularly in striatum . Interestingly, the frequency of CAG contractions increases in brain tissues and liver from mice with more than 500 CAG repeats  and could also explain the progressive reduction of neurological symptoms and prolonged lifespan in R6/2 mice with >200 CAG repeats [47–49]. Somatic instability has been noticed in dividing cells suggesting a role of DNA replication in the dynamic of triplet repeat instability. However, an increase of CAG repeat length has also been reported in terminally differentiated neurons from R6/1 mice suggesting the role of cellular processes independent of DNA replication in the somatic mosaicism . Recently, an effect of mouse genetic backgrounds on the dynamics of CAG expansions has been reported in tissues from R6/1 mice with high CAG somatic mosaicism on a B6 background and low level in BALB/cBy backgrounds suggesting the existence of genetic modifiers of instability .
2.2. HdhQ92‐111 mouse models
The first knock‐in mice called HdhQ50 have been generated in 1997 using homologous recombination in ES cells to replace short murine CAG repeat by 48 CAG repeats in 129SvEv/CD1 mice . In 1999, three other knock‐in mouse models (HdhQ20, HdhQ92 and HdhQ111) using the same strategy have been generated with 18, 90 and 109 CAG repeat tracts, respectively . These four knock‐in mice share the identical murine genomic environment (91% of similarities with
Somatic CAG repeat variations have been observed in HdhQ92 and HdhQ111 mice in brain and some peripheral tissues with the highest accumulation of expansions in striatum and liver [24, 56, 57]. Both these tissues showed a bimodal distribution of repeat lengths compared to spleen and tail that showed a unimodal distribution . CAG expanded alleles were broadly distributed in striatum compared to liver that showed distinct populations of CAG repeat expansions . Somatic instability depends on the CAG repeat size and the age of animals and is tissue‐specific as reported in R6 mice [24, 56, 57]. The relationship between somatic mosaicism and HD phenotype remains unclear but some data have reported that somatic mosaicism is not correlated with the initiation of disease but may be correlated with the progression of HD phenotypes [57, 58].
In conclusion, HD mouse models closely reproduced the dynamic of instability observed in HD patients. Intergenerational instability is biased toward expansions and depends on the CAG repeat length and the sex of transmitting parent. HD transgenic and knock‐in mouse models also mimic the somatic instability of HD patients, with the highest somatic mosaicism in the striatum that is the most affected tissue in HD. Some differences in the dynamics of intergenerational instability between HD patients and HD mouse models can be noticed. Despite a high level of instability biased toward expansions in paternal transmissions and contractions in maternal transmissions in both species, the critical CAG repeat threshold length differs between human and mice corresponding to 35 CAG repeats in human and more than 80 CAG repeats in mice. Moreover, no spontaneous large CAG repeat expansion has been observed in HD mouse models during paternal transmissions, in contrast to HD patients. These differences may be explained by genetic and environmental factors. Despite these divergences, the development of HD mouse models provided a powerful tool to explore trinucleotide repeat dynamics. Several data have suggested that the size, sex and the age factors are not sufficient to explain the level of meiotic and mitotic instabilities observed in HD patients and mice supporting the contribution of genetic modifiers in CAG repeat instability processes. Among described mouse models, R6 and HdhQ111 were commonly used to investigate the role of genetic modifiers on the level of intergenerational and somatic instability in HD.
3. Genetic modifiers of CAG repeat instability
The absence of correlation between CAG repeat somatic mosaicisms and the corresponding tissue proliferative rates and the destabilization of CAG repeat in murine mature neurons support the involvement of DNA repair pathways in the CAG repeat instability processes (Table 2). To identify the DNA repair pathways involved in the germline and somatic CAG repeat instability, R6/1 or HdhQ111 mice were crossed with mouse lines deficient for individual DNA repair genes. CAG repeat length changes upon transmissions were determined by comparing the CAG repeat size in the HD transmitting mice with CAG repeat length in the HD progeny for each DNA repair genotype (+/+ to +/+ and -/- to -/- and/or +/- to +/-). Furthermore, different methods have been described to quantify the degree of somatic instability and have made it possible to compare the level of somatic mosaicism between HD mice mutated and not for DNA repair genes [53, 57, 59–61].
|Gene modifiers||DNA repair
|Gene status||Mouse models||Effect on CAG repeat length||References|
|Intergenerational instability||Somatic instability|
|MMR||KO||HdhQ111||CAG repeat stabilization||[58, 67]|
|No change (female transmissions)|
|R6/1||No expansion (male transmissions) ND (female transmissions)||[59, 63]|
|HdhQ111||No significant change||CAG repeat stabilization|||
|KO||HdhQ111||No change (
|BER||R6/1||No change||[65, 70]|
|ND (female transmissions)||No change|||
3.1. Genetic modifiers of intergenerational instability
Despite some controversial results, the analyses in
The involvement of base excision repair (BER) and nucleotide excision repair (NER) in CAG repeat instability have been tested in R6/1 mice bred in a BER gene (
In conclusion, these data have shown that MSH2 and NEIL1 proteins are involved in the formation of intergenerational repeat expansions in HD mouse models with the highest effect of MSH2, suggesting that these genes are genetic modifiers of intergenerational instability in HD. Moreover, the shift toward contractions observed in the absence of
3.2. Genetic modifiers of somatic mosaicism
The analysis of CAG repeat instability has revealed a relationship between the severity of HD phenotypes and the level of expansion‐biased somatic mosaicism in patients and mice. Thus, HD mouse models in DNA repair deficient background have also been used to identify genetic modifiers of somatic instability. In R6/1 and HdhQ111 mice,
Compared to the results obtained in
To identify other genetic modifiers of CAG repeat instability, linkage analyses have been performed in different HdhQ111 strains that showed CAG repeat instability variation . A single quantitative trait locus on chromosome 9 and particularly in MutL homolog
Other DNA repair systems, such as BER and NER have also been investigated in R6/1 mice to understand the somatic expansion variation observed between and within tissues. A loss of
In conclusion, MSH2 and MSH3, partner proteins in the MutSβ MMR complex and MutLγ (MLH1‐MLH3) are essential to promote expansions in HD mouse models suggesting that MutSβ and MutLγ promote CAG expansion via the mismatch repair machinery. Furthermore, CAG repeat expansion depends only partially on OGG1, NEIL1 and FEN1 proteins suggesting that other DNA repair pathways are involved in the process of instability. Some genetic modifiers such as
4. Are genetic modifiers a therapeutic target?
The identification of genetic modifiers of underlying CAG repeat instability is important to uncover novel therapeutic targets to slow down somatic instability and to decrease the intergenerational expansions in favor of CAG repeat contractions to prevent the disease. It has been reported that
The data summarized in this chapter have shown that
The authors thank Geneviève Gourdon, Mario Gomes‐Pereira and Diana Dinca for helpful comments and discussions. The authors also thank Christopher Pearson group, HD/CAG.CTG repeat colleagues, Canadian Institutes of Health Research, Imagine institute, INSERM, the Association Française contre les Myopathes (AFM) and the université Paris Descartes.
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