Schizophrenia Daily News Blog

MECP2 Gene in Autistic-Spectrum Disorders and Childhood-Onset Schizophrenia

The MECP2 gene creates a protein which in turn regulates other genes. A defect in the MECP2 gene causes a potentially deadly autistic-spectrum disorder called Rett Syndrome. Mutations in this gene have also been associated with childhood-onset schizophrenia, classic autism, and learning disabilities.

The Rett Syndrome Research Foundation (RSRF) issued a press release announcing the reversal of symptoms of Rett Syndrome in a genetic mouse model. It is hoped that further research in this area will help children suffering from Rett syndrome as well as other neuropsychiatric disorders, such as childhood-onset schizophrenia, involving a defect in the MECP2 gene.

Below is the press release issued by the RSRF.

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The Rett Syndrome Research Foundation (RSRF) announces results of a landmark study reversing the symptoms of Rett Syndrome (RTT) in a genetic mouse model. The findings, by Adrian Bird, Ph.D., of the University of Edinburgh and Chairman of the RSRF Scientific Advisory Board, appear online in Science Express on February 8, 2007. Rett Syndrome is a severe childhood neurological disease that is the most physically disabling of the autism spectrum disorders. The experiments were funded by the Rett Syndrome Research Foundation (RSRF), the Wellcome Trust and the Rett Syndrome U.K./Jeans for Genes.

Caused by mutations in the gene MECP2, RTT affects primarily girls, striking at random in early childhood and destroying speech, normal movement and functional hand use. Many children become wheelchair bound; those who walk display an abnormal, stiff-legged gait. Disordered breathing patterns and Parkinson-like tremors are common.

Restoration of fully functional MECP2 over a four week period eradicated tremors and normalized breathing, mobility and gait in mice that had previously been fully symptomatic and, in some cases, only days away from death.

"Like many other people, we expected that giving MECP2 to mice that were already sick would not work," said Bird. "The idea that you could put back an essential component after the damage to the brain is done and recover an apparently normal mouse seemed farfetched, as nerve cells that developed in the absence of a key component were assumed to be irrevocably damaged. The results are gratifyingly clear, though, and must give hope to those who are affected by this distressing disorder."

Bird is Buchanan Professor of Genetics at University of Edinburgh and Director of the Wellcome Trust Centre for Cell Biology. MECP2, first identified by Bird in 1990, is considered to be a protein that regulates the expression of other genes by turning them off at the appropriate time.

In 1999 Huda Zoghbi, M.D., Professor, Departments of Molecular and Human Genetics, Pediatrics, Neurology, and Neuroscience at Baylor College of Medicine discovered that RTT is caused by mutations in the MECP2 gene. Mutations in MECP2 are now being seen in some cases of childhood schizophrenia, classic autism and learning disabilities.

"The findings are extraordinary, and are of relevance not only to Rett Syndrome but to a much broader class of disorders, including autism and schizophrenia. The successful restoration of normal function demonstrated in the mouse models suggests that if we can develop therapies to address the loss of MECP2 we may be able to reverse neurological damage in children and adults with Rett, autism and related neuropsychiatric disorders," commented Zoghbi.

The reversal experiments were carried out in the Bird lab by research assistant Jacky Guy. Employing technology known as Cre-lox recombination, she created mouse models in which MECP2 was silenced by insertion of a Stop cassette into the gene, resulting in the neurological deficits seen in RTT. Silencing could be reversed at will by removing the Stop cassette, thereby reactivating the MECP2 gene. This was achieved by treating the mice with a drug that caused the enzyme Cre to enter the cell nucleus where it could splice out the cassette.

As well as losing overt behavioral defects, the mice also recovered a key electrophysiological function of the brain. This was determined by measuring LTP (long-term potentiation) which provides a quantifiable measurement of the ability of neurons to respond to stimulation. LTP has long been thought to reflect the cellular basis of learning and memory. Though LTP in RTT mice models was defective, it was restored to normal function by the reversal experiments.

"The reversal of neurological defects, reported in the remarkable article by Guy et al, is surprising because the cause of the symptoms occurred early in development and was expected to be permanent. Of particular note is the recovery of LTP, which is the best current physiological correlate of learning and memory. These findings are very encouraging for those searching for a treatment because they give hope that the symptoms could not only be halted from progressing, but the course of the disease itself may be able to be reversed," stated Fred Gage, Ph.D. of the Salk Institute of Biological Studies.

"Dr. Bird's astonishing results usher in a new era for Rett Syndrome and other autism spectrum disorders. The reversal experiments provide justification for aggressive exploration of next steps on all fronts, from drug discovery to gene correction. The Rett Syndrome Research Foundation will be focused on a comprehensive effort to identify and speed treatments to the children and adults in dire need of them," commented Monica Coenraads, co-founder and Director of Research for RSRF and mother of a young daughter with the disorder.

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Press Release Source with Video: Reversal of Symptoms in Autism Spectrum Disorder

Additional Reading: Schizophrenia Genetics, Imprinting