Abstract

Fragile X syndrome (FXS) is caused by the maternal expansion of an unstable CGG-repeat tract located in the first exon of the FMR1 gene. Further changes in repeat number occur during embryogenesis resulting in individuals sometimes being highly mosaic. Here we show in a mouse model that, in males, expansions are already present in primary spermatocytes with no additional expansions occurring in later stages of gametogenesis. We also show that, in females, expansion occurs in the post-natal oocyte. Additional expansions and a high frequency of large contractions are seen in two-cell stage embryos. Expansion in oocytes, which are non-dividing, would be consistent with a mechanism involving aberrant DNA repair or recombination rather than a problem with chromosomal replication. Given the difficulty of replicating large CGG-repeat tracts, we speculate that very large expanded alleles may be prone to contract in the mitotically proliferating spermatagonial stem cells in men. However, expanded alleles may not be under such pressure in the non-dividing oocyte. The high degree of both expansions and contractions seen in early embryos may contribute to the high frequency of somatic mosaicism that is observed in humans. Our data thus suggest an explanation for the fact that FXS is exclusively maternally transmitted and lend support to models for repeat expansion that are based on problems arising during DNA repair.

Highlights

  • The fragile X-related disorders (FXDs) result from intergenerational expansions or increases in the number of CGG-repeats in a tandem repeat tract located downstream of the transcription start site of the fragile X mental retardation gene (FMR1; MIM ∗309550)

  • In this study we examined the timing of expansion during intergenerational transmission of FX PM alleles in a mouse model

  • We showed that expansions occur during male and female gametogenesis as well as in the early embryo

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Summary

Introduction

The fragile X-related disorders (FXDs) result from intergenerational expansions or increases in the number of CGG-repeats in a tandem repeat tract located downstream of the transcription start site of the fragile X mental retardation gene (FMR1; MIM ∗309550). Female PM carriers are at risk of transmitting an FMR1 allele with >200 repeats to their children. Carriers of such full mutation (FM) alleles have fragile X syndrome (FXS; MIM #300624), the most common. We have generated a mouse model of the FX PM that shows repeat instability reminiscent of what is seen in human PM carriers. This includes having a strong expansion bias and a dependence of these expansions on transcription or the presence of the PM alleles on the active X chromosome (Lokanga et al, 2013). Work from other related human Repeat Expansion Disorders suggests that expansions are dependent on some of the same mismatch repair factors that we have shown to be essential for expansion in the PM mouse (Du et al, 2012; Lokanga et al, 2014b; Zhao et al, 2015)

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