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Mechanisms of the CAG Repeat Mutation in Spinocerebellar Ataxia Type 1 Cara Kraus-Perrotta1 and Sarita Lagalwar2*

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Mechanisms of the CAG Repeat Mutation in Spinocerebellar Ataxia Type 1 Cara Kraus-Perrotta1 and Sarita Lagalwar2* Kraus-Perrotta and Lagalwar Cerebellum & Ataxias (2016) 3:20 DOI 10.1186/s40673-016-0058-y REVIEW Open Access Expansion, mosaicism and interruption: mechanisms of the CAG repeat mutation in spinocerebellar ataxia type 1 Cara Kraus-Perrotta1 and Sarita Lagalwar2* Abstract Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that primarily affects the cerebellum and brainstem. The genetic mutation is an expansion of CAG trinucleotide repeats within the coding region of the ataxin-1 gene, characterizing SCA1 as a polyglutamine expansion disease like Huntington’s. As with most polyglutamine expansion diseases, SCA1 follows the rules of genetic anticipation: the larger the expansion, the earlier and more rapid the symptoms. Unlike the majority of polyglutamine expansion diseases, the presence of histidine interruptions within the polyglutamine tract of ataxin-1 protein can prevent or mitigate disease. The present review aims to synthesize three decades of research on the ataxin-1 polyglutamine expansion mutation that causes SCA1. Data from genetic population studies and case studies is gathered along with data from manipulation studies in animal models. Specifically, we examine the molecular mechanisms that cause tract expansions and contractions, the molecular pathways that confer instability of tract length in gametic and somatic cells resulting in gametic and somatic mosaicism, the influence of maternal or paternal factors in inheritance of the expanded allele, and the effects of CAT/histidine interruptions to the ataxin-1 allele and protein product. Our review of existing data supports the following conclusions. First, polyCAG expansion of gametic alleles occur due to the failure of gap repair mechanisms for single or double strand breaks during the transition from an immature haploid spermatid to a mature haploid sperm cell. Equivalent failures were not detected in female gametic cells. Second, polyCAG expansion of somatic alleles occur due to hairpins formed on Okazaki fragments and slipped strand structures due to failures in mismatch repair and transcription-coupled nucleotide excision repair mechanisms. Third, CAT trinucleotide interruptions, which code for histidines in the translated protein, attenuate the formation of slipped strand structures which may protect the allele from the occurrence of large expansions. Many of the mechanisms of expansion identified in this review differ from those noted in Huntington’s disease indicating that gene -or sequence- specific factors may affect the behavior of the polyCAG/glutamine tract. Therefore, synthesis and review of research from the SCA1 field is valuable for future clinical and diagnostic work in the treatment and prevention of SCA1. Background atrophy, dentatorubral-pallidoluysian atrophy, and the Trinucleotide repeat disorders include a number of pro- spinocerebellar ataxias type 1, 2, 3, 6, 7, and 17 [1]. gressive neurodegenerative disorders caused by the First characterized by John Schut in 1950, spinocere- expansion of microsatellite repeat regions in coding and bellar ataxia type 1 (SCA1) is an autosomal dominant non-coding regions of specific genes. Polyglutamine neurodegenerative disease characterized by progressive diseases represent a subset of these disorders in which ataxia and eventual deficits with eye movement, speech, the repetitive sequence presents as CAG repeats. There and swallowing [2]. Symptoms are accompanied by are presently nine known polyglutamine disorders: degeneration in cerebellar Purkinje neurons and brain- Huntington’s disease, spinal and bulbar muscular stem nuclei [3]. Disease onset typically occurs during adulthood, * Correspondence: [email protected] between the ages 30 and 50, although cases of juvenile 2Neuroscience Program, Skidmore College, 815 North Broadway, Saratoga Springs, NY 12866, USA onset do occur. Life expectancy after disease onset is Full list of author information is available at the end of the article © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kraus-Perrotta and Lagalwar Cerebellum & Ataxias (2016) 3:20 Page 2 of 11 generally 10–20 years [4]. The polyCAG mutation is lo- sequence 69 % of the time; on average, maternal transmis- cated in the coding region of the ATXN1 gene on sion resulted in a contraction by −0.4 repeats [11]. Jodice chromosome 6 [4]. Normal alleles contain 6–44 CAG et al. found that expansions larger than 54 repeats were repeats, along with 1–3 CAT interruptions [5, 6]. only transmitted by males. On average, paternal transmis- Pathogenic alleles require a minimum expansion of sions resulted in an increase of +1.75 CAG repeats and 39 repeats [7]. Alleles containing 36–44 CAG repeats maternal transmissions resulted in a contraction of −0.5 interrupted by CATs are typically non-pathogenic, CAG repeats [12]. In an investigation of the frequency of whereas a similar range of CAGs without interrup- meiotic instability in transmission of SCA1, Ranum et tions generally confer pathogenesis [7, 8]. Age of on- al., calculated that roughly 82% of male transmissions set is inversely correlated with disease severity and and 60 % of female transmissions result in instability trinucleotide repeat length. Moreover, disease severity [13].Therefore,thedirection and frequency of in- and trinucleotide repeat length often increase in sub- stability differs by sex. sequent generations, a form of repeat instability that is indicative of genetic anticipation [4]. Male gametic instability The CAG mutation of SCA1 presents a unique case Mosaicism refers to an individual having genetically di- study for polyglutamine repeat disorders, as it is one of verse cells within the same tissue [14, 15]. In respect to only two polyglutamine disorders known to be mediated SCA1, ATXN1 genes harbor differentially sized repeat by interruptions in the repeat tract [9]. This review aims expansions. Chong et al. conducted PCR analysis of to synthesize the intergenerational and intra-generational blood and sperm samples from two SCA1 affected males manifestations of repeat instability in SCA1, as well as the and demonstrated that SCA1 alleles in sperm cells dis- effect of CAT/histidine interruptions at the DNA and play greater instability than blood cells [15]. Zulkhe et al. protein level. investigated mosaicism in four SCA1 affected males and found mosaicism in the sperm of one; however, the Intergenerational expansions in SCA1: anticipation researchers were unable to reach conclusions regarding Introduction the other individuals due to degraded samples [16]. A unique phenomenon of trinucleotide repeat disorders Therefore, although based on limited data, there was is intergenerational instability, often manifesting as an- early molecular evidence for instability of ATXN1 in the ticipation, or the worsening of the disease in subsequent male germline. generations. The molecular theory underlying anticipa- Evidence for male gametic instability influencing the tion became clear after the initial identification of trinu- expansion of CAG repeats can be found through cleotide repeat expansions in Fragile X Syndrome [10]. Huntington’s disease (HD) studies. Telenius et al. [17] A simple explanation seemed to appear: the longer the investigated paternal transmission of HD, and sought to repeat mutation, the more severe the disease. Conse- identify if a relationship exists between the extent of mo- quently, the mechanisms underlying the non-Mendelian saicism and intergenerational CAG repeat expansions inheritance patterns of CAG repeat disorders are of [17]. A significant association was found between the interest. In particular, the size and direction of the in- level of spermatic mosaicism in the male proband and stability appears to be influenced by parental sex, focus- the direction of intergenerational CAG repeat changes ing research on anticipation towards germline changes between the parent and the proband; lower levels of mo- in sperm. saicism correlated with CAG repeat contractions and greater mosaicism correlated with CAG repeat expan- Paternal versus maternal transmission sions or no change [17]. Therefore, the clinical evidence On the heels of the Fragile X and subsequent Hunting- that paternal transmissions result in larger CAG expan- ton’s discovery (Huntington’s Disease Research Collabora- sions is supported by the molecular evidence of gametic tive, 1993) was the observation in SCA1 that there are mosaicism in males. larger repeat expansions within paternally transmitted ataxin-1 (ATXN1) genes. Orr et al. first noted in 1993 that all known juvenile cases of SCA1, like HD, were paternally Developmental timing of expansions inherited [4]. Further research by Chung et al. quantified As outlined in Usdin et al.’s [18] review, there are the difference between maternal and paternal transmission multiple theoretical time points at which the intergener- of SCA1 in regard to the size of the repeat expansion. ational repeat expansions could occur: sperm
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