Scrutinizing the first days of development in abnormal embryonic stem cells, researchers have uncovered a basic mechanism underlying fragile X syndrome, the most common inherited cause of mental retardation in boys.
“It could have important implications for treatment,” says W. Ted Brown, cochair of the scientific committee of the National Fragile X Foundation, which helped fund the work.
The research also highlights the value of embryonic stem cells for studying genetic diseases, says Yang Xu, a stem cell researcher at the University of California, San Diego.
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Fragile X syndrome is caused by a mutation in a gene called fmr1. By stopping the gene from making its protein, the mutation leads to learning disabilities, elongated facial features, speech and language difficulties, emotional problems, and other symptoms. In boys, who have only one copy of the X chromosome, a single bad fmr1 gene inherited from either parent induces the disorder. Fragile X syndrome more rarely affects girls, who have two X chromosomes.
While researchers have long known that the fragile X mutation shuts down the gene, they were unsure how or at what developmental stage the disruption occurs. To study the shutdown, Nissim Benvenisty and his colleagues at the Hebrew University in Jerusalem created three embryonic stem cell lines carrying the mutation.
The cells came from embryos donated by couples with a family history of fragile X syndrome who visited an Israeli in vitro fertilization (IVF) clinic. Many IVF clinics now offer pre-implantation genetic diagnosis (PGD), which identifies genetically flawed embryos.
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To do a PGD, technicians pluck one cell out of a 3-day-old, eight-cell embryo. Tests then reveal whether the cell—and hence the embryo—carries specific mutations. If it does, the embryo normally is “discarded immediately,” says Benvenisty. But his team instead received consent from the couples to study any embryos carrying the fragile X mutation. The team grew several such embryos for about 5 days—to a stage called a blastocyst—and then teased stem cells out of the structure’s inner wall.
Despite carrying the fragile X mutation, the embryonic cells unexpectedly produced the fmr1 protein. “We were extremely surprised,” says Benvenisty. But when the team prodded the cells to begin developing into a range of tissues, the gene promptly shut down. “The [mutation] itself is not sufficient for the gene silencing,” says Benvenisty. “Something happens during development.”
Delving further, the team determined that changes in the gene’s wrapper, a structure called chromatin, switched off the gene. Those changes occur only after cells grow out of their embryonic state, presenting a window of opportunity for drug therapy, says Benvenisty. In addition, chromatin is easier to modify than the gene itself. His team is now screening drugs that might prevent the gene silencing by fixing the chromatin.
Other teams have created stem cells from embryos carrying genetic diseases, but Xu says that this is the first time the method has yielded a fundamental disease discovery. The study appears in the November Cell Stem Cell.
This article referred to boys inheriting a defective gene on the X chromosome from either parent. In fact, the X chromosome in males can come only from the mother. Also, the research described in the story was done by scientists at the Tel Aviv Sourasky Medical Center as well as the Hebrew University in Jerusalem.