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

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder characterized by neurodegeneration of the cerebellum, spinal cord and brainstem. A 1.2-Megabase stretch of DNA from the short arm of chromosome 6 containing the SCA1 locus was isolated in a yeast artificial chromosome contig and subcloned into cosmids. A highly polymorphic CAG repeat was identified in this region and was found to be unstable and expanded in individuals with SCA1. 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. We also show that the repeat is present in a 10 kilobase mRNA transcript. SCA1 is therefore the fifth genetic disorder to display a mutational mechanism involving an unstable trinucleotide repeat.

Genetic background of Huntington disease in Croatia: Molecular analysis of CAG, CCG, and ?2642 (E2642del) polymorphisms

“…We suggest that there may be the DNA sequences that influence the stability of the CAG repeat region in the HD gene on these chromosomes. In addition, loss of triplets, other than CAG, within the CAG repeat region could make this sequence more unstable and liable to expansion, as was previously found in fragile X syndrome and spinocerebellar ataxia type 1 (Orr et al, 1993). On the other hand, enrichment of the B7 haplotype among HD patients (40.5%) compared to controls (8.8%) could be explained by the finding that normal chromosomes with this haplotype have a significantly higher mean number of CAG repeats compared to other normal chromosomes (Table 3), suggesting that they could represent a subgroup of unstable normal alleles prone to expansion that eventually would result in CAG repeat allele within the HD range.…”

Spinocerebellar ataxia 1 (SCA1) in the Japanese: Analysis of CAG trinucleitide repeat expansion and instability of the repeat for paternal transmission

“…According to Orr et al (1993), polymerase chain reaction (PCR) amplification of CAG containing segments was done with Rep-1 and Rep-2 primer pairs. These oligonucleotide primers were synthesized using a DNA synthesizer (Model 380 B, Applied Biosystems).…”

Unstable expansion of triplet repeats as a new disease mechanism for neurodegenerative diseases

“…Expansion of CAG repeats in protein coding regions was first identified as the causative gene for spinal and bulbar muscular atrophy (SBMA) (La Spada et al, 1991). Since then expansion of CAG repeats in protein coding regions has been identified in Huntington's disease (HD) (The Huntington's Disease Collaborative Research Group, 1993), spinocerebellar ataxia type 1 (SCA1) (Orr et al, 1993), dentatorubral-pallidoluysian atrophy (DRPLA) (Koide et al, 1994;Nagafuchi et al, 1994a) and Machado-Joseph disease (MJD) (Kawaguchi et al, 1994) (Fig. 1).…”

“…As mentioned above, to date five diseases have been identified to be caused by unstable expansion of CAG repeats including SBMA, HD, SCA1, DRPLA and MJD (La Spada et al, 1991;The Huntington's Disease Collaborative Research Group, 1993;Orr et al, 1993;Koide et al, 1994;Nagafuchi et al, 1994a;Kawaguchi et al, 1994). The mode of inheritance of these diseases is autosomal dominant one except for SBMA which is inherited as an X-linked recessive trait.…”