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

      Nature genetics

      Base Sequence, Chromosome Mapping, Chromosomes, Human, Pair 6, Cloning, Molecular, DNA, genetics, Female, Humans, Male, Molecular Sequence Data, Oligodeoxyribonucleotides, Pedigree, Polymerase Chain Reaction, Repetitive Sequences, Nucleic Acid, Spinocerebellar Degenerations, Transcription, Genetic

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          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.

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          Most cited references 26

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          A second-generation linkage map of the human genome.

          A linkage map of the human genome has been constructed based on the segregation analysis of 814 newly characterized polymorphic loci containing short tracts of (C-A)n repeats in a panel of DNAs from eight large families. Statistical linkage analysis placed 813 of the markers into 23 linkage groups corresponding to the 22 autosomes and the X chromosome; 605 show a heterozygosity above 0.7 and 553 could be ordered with odds ratios above 1,000:1. The distance spanned corresponds to approximately 90% of the estimated length of the human genome.
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            Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member

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              Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n.

              The sequence of a Pst I restriction fragment was determined that demonstrate instability in fragile X syndrome pedigrees. The region of instability was localized to a trinucleotide repeat p(CCG)n. The sequence flanking this repeat were identical in normal and affected individuals. The breakpoints in two somatic cell hybrids constructed to break at the fragile site also mapped to this repeat sequence. The repeat exhibits instability both when cloned in a nonhomologous host and after amplification by the polymerase chain reaction. These results suggest variation in the trinucleotide repeat copy number as the molecular basis for the instability and possibly the fragile site. This would account for the observed properties of this region in vivo and in vitro.
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                Author and article information

                Journal
                8358429
                10.1038/ng0793-221

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