The alteration of a single nucleotide could initiate fragile X syndrome (FXS) by inactivating a replication origin, Gerhardt et al. reveal.

FXS is the most common inherited form of mental retardation and is caused by the expansion of a series of CGG repeats in the 5ʹ untranslated region of the FMR1 gene. Mothers carrying the FXS premutation have 55–200 repeats, but, during oogenesis or early embryogenesis, the number of repeats can expand until the FMR1 gene is silenced. Gerhardt et al. previously found that a replication origin located ∼50 kb upstream of the CGG repeats is inactivated in FXS embryonic stem cells. The majority of the repeats are therefore replicated from the opposite direction, which could pose problems that lead to repeat expansion.

Intriguingly, a single-nucleotide polymorphism (SNP) linked to an increased risk of repeat expansion has also been identified ∼50 kb upstream of the repeat locus in FXS patients within haplogroup D. Gerhardt et al. discovered that this SNP is located within the replication origin inactivated in these FXS embryonic stem cells.

Normal embryonic stem cells had an active replication origin and a thymine base at the SNP locus. FXS cells, in contrast, had a cytosine base and an inactive origin. The researchers also derived embryonic stem cells from mothers carrying the FXS premutation. These cells had a thymine base and a normal replication pattern and, accordingly, showed no tendency to expand their repeat number over time.

The substitution of cytosine for thymine therefore appears to inactivate the replication origin during oogenesis/early embryogenesis, increasing the risk of repeat expansion and FXS. The authors now want to investigate whether the critical replication origin is reactivated later in development, which would explain why the number of CGG repeats stabilizes in adult tissues.

, et al
J. Cell Biol
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Author notes

Text by Ben Short