Mitotic and meiotic instability of the CAG trinucleotide repeat in spinocerebellar ataxia type 1

  title={Mitotic and meiotic instability of the CAG trinucleotide repeat in spinocerebellar ataxia type 1},
  author={Pernille Koefoed and L. Hasholt and Kirsten Fenger and J{\o}rgen Erik Nielsen and Hans Eiberg and Karsten Buschard and Sven Asger S{\o}rensen},
  journal={Human Genetics},
Spinocerebellar ataxia type 1 (SCA1) is an autosomal, dominantly inherited neurodegenerative disease caused by an unstable CAG trinucleotide repeat expansion in the ataxin-1 gene located on chromosome 6p22-p23. The expanded CAG repeat is unstable during transmission, and a variation in the CAG repeat length has been found in different tissues, including sperm samples from affected males. In order further to examine the mitotic and meiotic instability of the (CAG)n stretch we have performed… 

Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2

An infantile SCA2 patient who, due to germ-line CAG repeat instability in her father, inherited an extremely expanded C AG repeat in theSCA2 locus, Surprisingly, the expanded allele of the father was an interrupted CAGrepeat sequence.

Instability of a premutation allele in homozygous patients with myotonic dystrophy type 1

The difference in the somatic stability of the (CTG)43 allele between the mother and her offspring suggests that interallelic interactions or other mechanisms in trans regulate the stability of a premutation allele.

CTG Trinucleotide repeat instability in escherichia coli

A model is proposed in which orientation-dependent CTG repeat instability in mismatch repair proficient cells is caused by the repair of 3-bp slippages, which may lead to the creation of larger deletions during repair synthesis due to the formation of unusual secondary structures by the CTG sequence on the lagging strand.

Factors involved in the initial mutation of the fragile X CGG repeat as determined by sperm small pool PCR.

To dissect the factors involved in the initial mutations of the CGG repeat, small pool (SP)-PCR was performed on DNA derived from sperm and blood from seven unaffected males whose repeat sizes range from 20 to 33 and regression analyses suggested that components of the repeat structure such as the number of interruptions and purity of the 3' end of therepeat are important determinants of germline repeat instability.

No association of the SCA1 (CAG)31 allele with Huntington's disease, myotonic dystrophy type 1 and spinocerebellar ataxia type 3

The findings do not support the hypothesis that this allele is involved in the etiology of trinucleotide expansion, and implicate a possible role of the SCA1 (CAG)31 allele in other triplet diseases.

Expansions of CAG.CTG repeats in immortalized human astrocytes.

Mechanistically, it was found that the direction of DNA replication through the TNR influenced the frequency of expansions, suggesting that either replication or a replication-associated process, such as DNA repair, contributes to CAG*CTG tract instability in SVG-A cells.

The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

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

Meiotic contraction of CAG repeats in Saccharomyces cerevisiae.

The results suggest that long CAG repeats are destabilized during meiosis or gametogenesis in S. cerevisiae.

Investigating the molecular and cellular basis of pathogenesis in Huntington's disease.

The alterations observed in HD knock-in mice occur in the absence of obvious cell loss, suggesting that this system maybe modelling the events involved in early HD pathogenesis.



Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1

There is a direct correlation between the size of the (CAG)n repeat expansion and the age–of–onset of SCA1, with larger alleles occurring in juvenile cases.

Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I

Spinocerebellar ataxia type I (SCAI) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat on chromosome 6p. Normal alleles range from 19–36 repeats

The molecular diagnosis of spinocerebellar ataxia type 1 in patients with ataxia

The hitherto longest normal uninterrupted allele of 22 repeat units is reported and the importance of analysis for the presence of CAT interruptions in the diagnosis of SCA1 is stressed.

Unstable triplet repeat and phenotypic variability of spinocerebellar ataxia type 1

A Siberian kindred with spinocerebellar ataxia genetically linked to theSCA1 locus on chromosome 6p has been screened for the CAG triplet expansion within the coding region of the SCA1 gene and Cerebellar deficiency was present in each patient and its severity was moderately affected by the number of CAG repeats.

Gametic and somatic tissue–specific heterogeneity of the expanded SCA1 CAG repeat in spinocerebellar ataxia type 1

The differences in SCA1 allele heterogeneity between sperm and blood and within the brain parallels the findings in Huntington disease, suggesting that both disorders share a common mechanism for tissue–specific instability.

Presymptomatic analysis of spinocerebellar ataxia type 1 (SCA1) via the expansion of the SCA1 CAG-repeat in a large pedigree displaying anticipation and parental male bias.

Analysis of the repeat expansion dramatically changes diagnosis of SCA1, a clinical and genetic heterogeneous neurodegenerative disorder which leads to progressive cerebellar ataxia which has been first localised to 6p and has been more recently characterised.

Single sperm analysis of the trinucleotide repeats in the Huntington's disease gene: quantification of the mutation frequency spectrum.

The CAG triplet repeat region of the Huntington's disease gene was amplified in 923 single sperm from three affected and two normal individuals and an excellent fit was found when the model specified that a random number of repeats are added during the progression of the polymerase through the repeated region.

CAG repeat length variation in sperm from a patient with Kennedy's disease.

Comparison of the SBMA sperm typing results with mutation frequency data on normal alleles supports the hypothesis that trinucleotide repeat expansions may have a different molecular origin than contractions.

Single sperm analysis of the CAG repeats in the gene for Machado-Joseph disease (MJD1): evidence for non-Mendelian transmission of the MJD1 gene and for the effect of the intragenic CGG/GGG polymorphism on the intergenerational instability.

Findings in single sperm confirm non-Mendelian transmission of the MJD1 gene and the effect of the intragenic CGG/GGG polymorphism on the intergenerational instability of the CAG repeats in the MJd1 gene, which have been observed in clinical and genetic studies.

Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses.

It is shown that IANM are more unstable than IAGP with identical size and sequence, and comparison of different sized IAs and IAs with different sequences between the CAG and the adjacent CCG tracts indicates that DNA sequence is a major influence on CAG stability.