Stem cells model disease

Embryonic stem cell study uncovers mechanism for Fragile X gene mutation

By | November 14, 2007

Researchers have used a line of embryonic stem cells carrying the mutation for Fragile X Syndrome, the most common genetic form of mental retardation, to determine when the altered gene exerts its effect during development, according to a study published online this week in Cell Stem Cell. The study, one of the first to use stem cells from an embryo afflicted with a genetic disorder, found that the mutated gene functions normally in early embryogenesis, but is silenced by cell differentiation. Their results suggest that stem cell studies may offer insights to disease pathogenesis that animal models cannot provide, the researchers say. The work "highlights the value of [human embryonic stem cells] as a model system for early human embryo development," the study's coauthor, Rachel Eiges of the Hebrew University in Jerusalem, told The Scientist. "We show that it can be used as a powerful tool to analyze the effect of a specific mutation on particular developmental events, allowing exploring processes which are otherwise inaccessible for research." Fragile X has been linked to a mutation in the Fragile X mental retardation 1 (FMR1) gene that blocks production of the FMR protein. But because animal and cellular models of the disorder do not recapitulate the molecular processes that take place during embryogenesis, researchers have been unable to pinpoint how and when the mutation disrupts the gene's function. To address this question, Eiges' team generated a line of human embryonic stem cells from an embryo identified by preimplantation genetic diagnosis to have the Fragile X mutation. Using RT-PCR and Western blot analysis, they found that the undifferentiated stem cells normally transcribed the Fragile X gene and produced the FMR protein. But when the cells were induced to differentiate, both the FMR1 mRNA and FMR protein levels dropped significantly, suggesting that differentiation is necessary to trigger the silencing mutation and cause the symptoms of the disease. Further experiments showed that what flipped this trigger was post-translational modification: A protein involved in the structure of chromatin that has previously been shown to play a role in silencing genes was unmethylated in the undifferentiated stem cells, but became methylated upon differentiation. Methylation condenses the chromatin in the region of the FMR1 gene, preventing its transcription. The finding "demonstrates that FMR1 inactivation is a multi-step process, which is developmentally regulated and is triggered by differentiation," Eiges said. "Certainly, stem cell lines such as this will help science unravel the mechanisms associated with human genetic disorders, and hopefully lead to new therapeutic treatments and interventions in the future," said Robert Lanza of Advanced Cell Technology in Los Angeles, CA, who was not involved in the research. Such an approach has been overshadowed by the focus on developing stem cells as treatments for various disorders, he noted. M. William Lensch of Children's Hospital Boston, also not a coauthor, called the study "thrilling," but added that current restrictions on federally-funded stem cell research, which prohibit the creation of new stem cell lines, may be limiting this type of work. "This is a study that couldn't have happened in the U.S. unless it was completely funded by private money," Lensch said. Steve Mitchell Links within this article: The readers and editors of The Scientist, "Cracking cloning," The Scientist, June 1, 2006. R. Eiges et al., "Developmental Study of Fragile X Syndrome Using Human Embryonic Stem Cells Derived from Preimplantation Genetically Diagnosed Embryos," published online November 15, 2007. A. Gawrylewski, "The trouble with animal models," The Scientist, July 1, 2007. Rachel Eiges J. Roberts, "A new RNA disease?" The Scientist, August 15, 2007. C. Q. Choi, "Stem cells from a single cell?" The Scientist, August 23, 2006. R. Lewis, "Preimplantation genetic Diagnosis: The next big thing?" The Scientist, November 13, 2000. Robert Lanza M. William Lensch A. Harding, "US stem cell rules loosening?" The Scientist, May 20, 2004.


Avatar of: Sergio Stagnaro

Sergio Stagnaro

Posts: 59

November 15, 2007

I have just read with pleasure the article, that corroborate what I wrote in the mail posted in Wahington Post at URL \n\n, and re-posted even in Briefly, before utilizing stem cells of whatever origine, we have to know perfectly donor's all biophysical-semeiotic constitutions ( order to avoid other dangerous disorders, already underlyined, such as leucaemia and osteoporosis.

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