Fragile X Syndrome Mechanism discovered

Author:  Brittany Raffa
Date:  December 2007

Dr. Nissim Benvenisty and Dr. Rachel Eiges from the Hebrew University Department of Genetics in Jerusalem, Israel, and Dr. Dalit Ben-Yosef from the in vitro fertilization unit at the Tel-Aviv Sourasky Medical Center have determined the order of events that lead to Fragile X syndrome early in development by using a line of embryonic stem cells carryiwwwng the mutation for the syndrome. The results are published in the November issue of the journal Cell Stem Cell.

Fragile X syndrome is the major cause of inherited mental retardation and autism in boys. The mutation occurs in a gene called fmr1 that fails to make the FMR protein, a protein thought to be essential for the normal functioning of the brain. It happens less often in girls because they have two X chromosomes with the same genes so if one is impaired the other still functions. In contrast, boys have one X chromosome.

The team from the Hebrew University and the Tel-Aviv Sourasky Medical Center made a line of human embryonic stem cells from an embryo with the Fragile X mutation. The experiments revealed that undifferentiated stem cells, cells that have not yet become a specific type of cell, transcribe the FMR protein. However, when cells were forced to differentiate, or become a specific cell type, the level of FMR protein decreased substantially.

The scientists went even further by demonstrating that the inactivation of the gene is a post-translational modification, that is, the problem occurs after the process of making the protein. Chromatin is a complex in the nucleus that shortens to become chromosomes during cell division. A protein associated with the chromatin's structure that was previously known to aid in inactivating genes is unmethylated in the undifferentiated stem cells that work normally. After differentiation of the cells, the protein is methylated, causing the chromatin to condense in the region of the fmr1 gene, in turn preventing the gene from being copied into the protein. The result "demonstrates that the fmr1 inactivation is a multi-step process, which is developmentally regulated and is triggered by differentiation," explained Dr, Rachel Eiges, one of the researchers.

This is an opportunity for drug therapy because the inactivation of the gene occurs once the cells are no longer in the embryonic state and the methylated chromatin is easier to modify than the gene. Dr. Benvenisty's team is now screening drugs that could correct the chromatin.

The research accentuates the important functions of stem cells in the study of genetic diseases by offering a solution when animal models cannot. The work "highlights the value of [human embryonic stem cells] as a model system for early human embryo development," said Eiges.

M. William Lensch, Senior Researcher of the Stem Cell Program at Children's Hospital Boston, a worldwide leader in stem cell research, called the study "thrilling" but added that, due to current restrictions on federally-funded stem cell research, "This is a type of study that couldn't have happened in the U.S. unless it was completely funded by private money."

Written by Brittany Raffa

Reviewed by Emma Wear

Published by Pooja Ghatalia.