Zoghbi Lab Achieves Phenotype Reversal of MECP2 Gene Duplication in Mice Using Antisense Oligonucleotides (ASOs); Advance Heralds Possible Treatment of Human MECP2 Duplication Syndrome, Possibly Other Duplication Disorders

Gene duplications are a common cause of intellectual disabilities and autism, as well as various other neurological disorders. In a new study that was published online today (November 25, 2015) in Nature, Huda Zoghbi (photo), M.D., Professor of Molecular and Human Genetics at Baylor College of Medicine, and Director of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, and her team showed that there is a new potential way to treat such disorders. MECP2 (methyl-CpG-binding) protein is a cellular maestro, that modulates the expression of thousands of genes in the brain, but its levels must be carefully controlled. Too little of the protein results in Rett syndrome, a childhood neurological disorder characterized by decreased cognition, inability to perform motor functions, particularly with hands, and autism-like behavior. More than 10 years ago, Dr. Zoghbi who is also a Howard Hughes Medical Institute (HHMI) investigator, discovered that MECP2 is a "Goldilocks" protein - too little causes Rett syndrome, but too much can cause a different neurological problem. The mouse models that Zoghbi's lab generated with an extra copy of the MECP2 gene developed a progressive neurological disorder. Dr. Zoghbi suspected there must be children or adults with analogous neurological problems due to duplication of the MECP2 gene and this proved to be the case. Boys with the MECP2 duplication syndrome suffer from poor muscle tone and motor function, cognitive disability, epilepsy, autistic behaviors, respiratory infections, and premature death. Once considered rare, it appears that MECP2 duplication syndrome is more common than previously thought, said Yehezkel Sztainberg, Ph.D., a postdoctoral fellow in Zoghbi's laboratory and first author of the report.
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