Abstract
The Fragile X-related disorders (FXDs) are a group of clinical conditions resulting from the expansion of a CGG/CCG-repeat tract in exon 1 of the Fragile X mental retardation 1 (FMR1) gene. While expansions of the repeat tract predominate, contractions are also seen with the net result being that individuals can show extensive repeat length heterogeneity in different tissues. The mechanisms responsible for expansion and contraction are still not well understood. This review will discuss what is known about these processes and current evidence that supports a model in which expansion arises from the interaction of components of the base excision repair, mismatch repair and transcription coupled repair pathways.
Highlights
This year marks 25 years since the genetic basis of Fragile X syndrome (FXS) was shown to be the increase in size or expansion of a CGG/CCG-repeat tract in the 50 untranslated region of the Fragile X mental retardation 1 (FMR1) gene [1]
We know that expansion mutations are the cause of more than 30 different human genetic disorders including myotonic dystrophy type 1 (DM1), Huntington disease (HD) and Machado-Joseph disease/Spinocerebellar ataxia type 3 (MJD/SCA3) that, like spinal and bulbar muscular atrophy (SBMA), involve CAG/CTG repeats, as well as Friedreich ataxia (FRDA) that involves GAA/TTC
We will focus primarily on what we have learnt about repeat instability in FXS and the other FX-related disorders (FXDs), Fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI)
Summary
This year marks 25 years since the genetic basis of Fragile X syndrome (FXS) was shown to be the increase in size or expansion of a CGG/CCG-repeat tract in the 50 untranslated region of the Fragile X mental retardation 1 (FMR1) gene [1]. This expansion occurs from a predisposed premutation (PM) allele with 55–200 repeats to a full mutation (FM) allele that has at least 200 repeats and may have gained hundreds if not thousands of additional repeats. Both expansion and contraction are likely to contribute to the mosaicism seen in many carriers of FMR1 alleles with large repeat numbers
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