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Neurogenetics

Fragile X linked mental retardation is a paradigma of neurogenetic diseases caused by triplet repeat expansion. The repeat is located in the 5'-UTR and consists of CGGs. Affected individuals have 1000 or more repeat units and show abnormal methylation of regulatory sequences. Fully expanded repeats probably result during postzygotic length variation of maternally inherited premutations (60-200 units) in an early developmental window and result in mitotically stable patterns of different expansions (somatic mosaicism). The cause of the parental bias concerning expansion to full mutation is a long standing question.
New findings, which address factors responsible for the instability of triplet repeats in particular stages of development, were obtained from a comparison of the mitotic behaviours of expanded CGG-repeats in fragile X syndrome and CTG repeat expansions in myotonic dystrophy. In striking contrast to fragile X syndrome, large expansions in myotonic dystrophy were found mitotically unstable on identical cellular backgrounds. The unstable CTG repeat is embedded in an undermethylated genomic environment and is not methylated. DNA methylation is, hence, postulated to stabilize the expanded CGG repeat, most probably by providing secondary signals essential for an effective methyl-directed DNA mismatch repair. In the early development there is undermethylation of DNA sequences including CpG islands. This may result in transitory repeat instability and expansion to full mutation. In this early stage, methylation patterns of fragile X premutations may depend on parental origin. We are studying methylation patterns around stable and unstable triplet repeats and results will be presented.




Headings
DNA methylation
triplet repeat stability
CGG repeats
CTG repeat
Fragile X
myotonic dystrohy

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