September 30, 1999-- A 14-year search for the cause of a rare genetic disease that strikes young girls has uncovered the first example of a human disease linked to a defect in a mechanism designed to keep certain genes silent. This discovery may provide new insights into nervous system development in the fetus and young child.

Rett syndrome (RTT) is a neurodevelopmental disorder seen in young girls that causes a sudden and permanent decline in mental capabilities. In 1985, HHMI investigator Huda Zoghbi, who was then a neurology fellow, published a clinical research report on Rett syndrome. Her initial encounter with the disorder had a lasting impact on her career. Shortly after seeing her first RTT patients, Zoghbi decided to change her career plans, switching from clinical medicine to a research position. Shortly after switching to research, she started the long, tedious search for the genetic causes of RTT.

"Finding that gene is the hardest thing I've ever worked on," Zoghbi said in an interview. "It's the best case for the rewards of perseverance that I can think of."

The gene, called MECP2, resides on the far end of the longest arm of the X chromosome. MECP2 encodes a protein named methyl-CpG-binding protein 2, or MeCP2, that binds to genes that a cell has methylated. During development certain genes that are to be silenced, or prevented from being expressed, are physically marked by the addition of methyl groups. When bound to a methylated gene, MeCP2 facilitates gene silencing by attracting other proteins that prevent access to the cell's DNA transcription machinery.

Previous work by other researchers had shown that inactivating the mouse version of Mecp2 caused a lethal defect in male mouse embryos. Zoghbi's group at Baylor College of Medicine, in collaboration with researchers led by

Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
1-Oct-1999