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Mechanism of Fragile X Syndrome Revealed

The FMR1 gene uses a different origin of replication in Fragile X embryonic stem cellsFragile X syndrome (FXS) is caused by expansion of the CGG trinucleotide repeat in the Fragile X Mental Retardation gene, FMR1. FXS results in intellectual disability along with other physical and behavioral characteristics with males generally more severely affected. Normal individuals have CGG repeats ranging from 6 to 54 copies, but FXS patients frequently have over 200 copies, resulting in transcriptional silencing of the gene such that no protein is produced. The absence of FMR1 protein causes the characteristics of FXS, but CGG expansion is variable, leading to mosaicism within individuals and the range of characteristics seen in patients. Trinucleotide repeat expansion in the FMR1 gene is caused by instability in early development and during germ cell production and is thought to be a result of DNA polymerase slippage during DNA replication. However, several models have been proposed to account for the DNA slippage. Now, results published in Molecular Cell from a team led by Drs. Carl Schildkraut and Jeannine Gerhardt, at the Albert Einstein College of Medicine, examined DNA replication and the use of DNA origins of replication in normal and FXS human embryonic stem cells (hESCs). Using a method called SMARD, for single-molecule analysis of replicated DNA, the team observed that FXS hESCs use a different origin of replication, changing the direction of DNA replication through the FMR1 gene, than normal hESCs. This lends support to the “origin switch” model of slippage, in which DNA replication through the repeat region increases the formation of secondary structures – when a DNA strand binds to itself rather than the complimentary strand – thereby causing the DNA polymerase to slip and resulting in expansion of the CGG repeats. This is the first study to examine FXS and trinucleotide repeat expansion in human embryonic stem cells. This work was supported by a NYSTEM research award to Dr. Schildkraut (C024348) and a NYSTEM Shared Facilities award to collaborators at Memorial Sloan-Kettering Cancer Center (C024175).

Gerhardt J, Tomishima MJ, Zaninovic N, Colak D, Yan Z, Zhan Q, Rosenwaks Z, Jaffrey SR, Schildkraut CL. The DNA Replication Program Is Altered at the FMR1 Locus in Fragile X Embryonic Stem Cells. Mol Cell. 2014 Jan 9; 53(1):19-31.