Expansion, mosaicism and interruption: mechanisms of the CAG repeat mutation in spinocerebellar ataxia type 1

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.