Expansion, mosaicism and interruption: mechanisms of the CAG repeat mutation in spinocerebellar ataxia type 1 (original) (raw)
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Genetic Modifiers of CAG.CTG Repeat Instability in Huntington's Disease Mouse Models
2017
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 mosai...
De Novo Expansion of Intermediate Alleles in Spinocerebellar Ataxia 7
Human Molecular Genetics, 1998
Spinocerebellar ataxia 7 (SCA7) is the eighth neurodegenerative disorder caused by a translated CAG repeat expansion. Normal SCA7 alleles carry from four to 35 CAG repeats, whereas pathological alleles carry from 37 to ∼200. Intermediate alleles (IAs), with 28-35 repeats in the SCA7 gene are exceedingly rare in the general population and are not associated with the SCA7 phenotype, although they have been found among relatives of four SCA7 families. In two of these families, IAs bearing 35 and 28 CAG repeats gave rise, during paternal transmission, to SCA7 expansions of 57 and 47 repeats, respectively, that were confirmed by haplotype reconstructions in one case and by inference in the other. Furthermore, the four haplotypes segregating with IAs were identical to the expanded alleles in each kindred, but differed among the families, indicating multiple origins of the SCA7 mutation in these families with different geographical origins. Our results provide the first evidence of de novo SCA7 expansions from IAs that are not associated with the phenotype but can expand to the pathological range during some paternal transmissions. IAs that segregate in unaffected branches of the pedigrees might, therefore, constitute a reservoir for future de novo mutations that occur in a recurrent but random manner. This would explain the persistence of the disease in spite of the great anticipation (∼20 years/generation) characteristic of SCA7. So far, de novo expansions among the disorders caused by polyglutamine repeats have only been demonstrated in Huntington's disease.
Somatic expansion of the (CAG) n repeat in Huntington disease brains
Human Genetics, 1995
The mutation causing Huntington disease (HD) has been identified as an expansion of a polymorphic (CAG)n repeat in the 5" part of the huntingtin gene. The specific neuropathology of HD, viz. selective neuronal loss in the caudate nucleus and putamen, cannot be explained by the widespread expression of the gene. Since somatic expansion is observed in affected tissue in myotonic dystrophy, we have studied the length of the (CAG), repeat in various regions of the brain. Although we have not found clear differences when comparing severely and mildly affected regions, we have observed a minor increase in repeat length upon comparison of affected brain samples with cerebellum or peripheral blood. Hence, although further somatic amplification seems to occur in affected areas of the brain, the differences between affected and unaffected regions are too small to make this mechanism an obvious candidate for the cause of differential neuronal degeneration in HD.
Very Large (CAG)n DNA Repeat Expansions in the Sperm of Two Spinocerebellar Ataxia Type 7 Males
Human Molecular Genetics, 1999
Genetic anticipation, i.e. increasing disease severity and decreasing age of onset from one generation to the next, is observed in a number of diseases, including myotonic dystrophy type 1, Huntington's disease and several of the spinocerebellar ataxias. All of these disorders are associated with the expansion of a trinucleotide repeat and array length is positively correlated with disease severity and inversely correlated with the age of onset. The expanded repeat is highly unstable and continues to expand from one generation to the next, providing a molecular explanation for anticipation. Spinocerebellar ataxia type 7 (SCA7) is one of the latest additions to the list of triplet repeat diseases and is distinct from the other SCAs in that it is accompanied by retinal degeneration. Pedigree analyses have previously revealed that the SCA7 repeat is highly unstable and liable to expand, in particular when transmitted by a male. Surprisingly, though, an under-representation of male transmission has also been reported. We now demonstrate directly by single molecule analyses that the expanded repeat is extraordinarily unstable in the male germline and biased toward massive increases. Nearly all of the mutant sperm of two SCA7 males contain alleles that are so large that most of the affected offspring would at best have a severe infantile form of the disease. Indeed, the gross under-representation of such very large expanded alleles in patients suggests that a significant proportion of such alleles might be associated with embryonic lethality or dysfunctional sperm.
The effects of variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from huntingtin's polyglutamine segment, dictates the rate at which HD develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally-occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question a fundamental premise of the "polyglutamine disorders".
Rare Diseases, 2016
Huntington's Disease is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. Whether somatic expansion contributed to toxicity was unknown. From extensive work from multiple laboratories, it has been made clear that toxicity depended on length of the inherited allele, but whether preventing or delaying somatic repeat expansion in vivo would be beneficial was unknown, since the inherited disease allele was still expressed. In Budworth et al., we provided definitive evidence that suppressing the somatic expansion in mice substantially delays disease onset in littermates that inherit the same disease-length allele. This key discovery opens the door for therapeutic approaches targeted at stopping or shortening the CAG tract during life. The analysis was difficult and, at times, non-standard. Here, we take the opportunity to discuss the challenges, the analytical solutions, and to address some controversial issues with respect to expansion biology.
Human Molecular Genetics, 2000
Gender is known to influence the transmission of trinucleotide repeats in human disease. However, the molecular basis for the parent-of-origin effect associated with trinucleotide repeat expansion is not known. We have followed, during transmission, the fate of the CAG trinucleotide repeat in a transgene containing the exon 1 portion of the human Huntington's disease (HD) gene. Similar to humans, the mouse transmits expansions predominantly through the male germ line. Surprisingly, we find that the CAG repeat size of the mutant human HD gene is different in male and female progeny from identical fathers. Males predominantly expand the repeat whereas females predominantly contract the repeat. In contrast to the classic definition of imprinting, CAG expansion is influenced by the gender of the embryo. Our results raise the possibility that there are X-or Y-encoded factors that influence repair or replication of DNA in the embryo. Gender dependence in the embryo may explain why expansion in HD from premutation to disease primarily occurs through the paternal line.
Journal of Huntington's Disease
The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington’s disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions ha...