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Cure Autism Now Genius Award Recipient Discovers a New Role for the Gene Involved in Rett's Syndrome

What we may learn
October 14, 2007

The Cure Autism Now science program profiles several new publications that have emerged from the laboratory of Dr. Huda Zoghbi, and reports how ultimately these studies may be shedding new light on some of the cellular features of autism.

Elise Lamar, Ph.D.

Autistic behavior is a feature of many different disorders. One of these is the developmental disorder known as Rett's Syndrome (RTT). Along with Classic Autism and Asperger's Disorder, RTT is one of the five Pervasive Developmental Disorders listed by the DSM-IV manual. Beginning in toddlerhood, RTT is marked by deterioration of newly acquired motor skills, language deficits, retardation, seizures, and also by social and stereotyped behaviors reminiscent of autism.

In a landmark 1999 discovery, Huda Zoghbi, M.D., at Baylor College of Medicine in Houston, discovered that RTT is caused by mutations in the MeCP2 gene, which encodes a protein of the same name (MeCP2). MeCP2 binds to chromosomal DNA and shuts down or "silences" the activity of genes located where it binds. Mutant forms of MeCP2 made by RTT patients cannot perform this "silencing" activity. The fact that common behaviors are seen in both autism and RTT suggests that damage to pathways relevant to MeCP2 function could underlie some forms of autism. So promising is this connection that her studies earned Dr. Zoghbi a Genius Award from Cure Autism Now in 2004, allowing her to focus specifically on the biological link between MeCP2 function and autism. Mutations in MeCP2 may turn out to underlie only a subset of autism cases. Nonetheless, Dr. Zoghbi's studies reveal some of the underlying cellular and molecular processes that may be more globally affected.

Using the Genius Grant, Dr. Zoghbi's team reported in 2005 that mice deficient in MeCP2 (the mouse version of the human gene) show behaviors reminiscent of autism. These findings extended work begun three years ago when Dr. Zoghbi's group created an RTT animal "model" that they termed the MeCP2/308/Y mouse. The DNA of this mouse was engineered so that its cells make a shortened, or mutated, version of the MeCP2 protein. Such models are valuable tools to analyze the biochemical basis of any genetic disease because, as much as a mouse can, they resemble humans who make damaged proteins.

The MeCP2/308/Y mouse showed neurological symptoms of RTT, such as tremors and repetitive forepaw movements reminiscent of hand-wringing seen in RTT patients. When subjected to an extensive battery of behavioral tests, the MeCP2/308/Y mouse also displayed irregular social behaviors suggestive of autism, such as impaired nest-building and reluctance to approach or remain near other mice, showing that the MeCP2/308/Y mouse may serve as a genetic model for some features of autism. Also in 2004, a separate study from the group of Janine LaSalle, Ph.D., found that MeCP2 expression levels were indeed altered in tissues taken from individuals with autism, further demonstrating that damage to the MeCP2 pathway can be directly tied to autism.

Work by Dr. Zoghbi and other labs has led to a simple theory of how damaging MeCP2 might lead to neurodevelopmental disorders such as RTT and autism. Although all cells in the body contain virtually the same genes, generally speaking brain cells make a different array of proteins than do, for example, pancreatic cells. This occurs partly because brain cells make proteins that "silence" genes necessary to construct a pancreas, and pancreatic cells "silence" genes required to make a brain. Moreover within the brain, different genes are silenced at different times. In RTT, and possibly in autism, one protein doing the heavy lifting in the silencing process (MeCP2) is damaged such that it no longer works. When genes can't be turned off in a regulated manner they can interfere with proper neuronal function. What these genes are in the case of RTT or autism is currently not known, but currently it is an area of active investigation.

However, the Zoghbi lab has just added a new twist to this story. In another study funded by Cure Autism Now and published in December 2005 in the Proceedings of the National Academy of Science, her lab reports a novel role for MeCP2: in addition to "silencing" DNA, they showed that MeCP2 participates in a process known as "alternative splicing." To make cellular proteins, information encoded on DNA is first made into a linear molecule called messenger RNA (mRNA) and then literally cut up ("spliced") to make an assortment of different proteins. What Dr. Zoghbi's group showed is that in nerve cells, MeCP2 assists in this splicing process. They looked at a collection of over 20,000 spliced mRNAs from the brain of the MeCP2-308/Y mouse and compared them to mRNAs made in normal mouse brain.

Not only were there differences in splicing profiles in the two mice, but researchers could identify many of these differentially spliced genes. Among them were factors known to promote the growth of nerve cell precursors, and a gene known as dlx5, which is important for the development of inhibitory neurons in the brain. In an exciting convergence, in a new study using Cure Autism Now's AGRE collection, dlx5 itself has just been found mutated in a small number of patients with autism, again suggestive of common pathways that may ultimately play a role in autism.

These findings are exciting for basic researchers and clinicians alike. Biochemists now know that MeCP2, which was once believed to do only one thing, e.g., silencing, participates in yet another critical cellular activity, alternative splicing. And clinical researchers, whose jobs are to use this information to design cures, now have a better idea of what they are "curing." Cells, like appliances, generally can't be "fixed" until you know exactly what's wrong with them. Thanks to this latest work from Dr. Zoghbi's lab we know that at least one of two processes-silencing or splicing-could need repair in cells mutant in MeCP2 activity and thereby in the brain cells of patients with RTT and perhaps autism.

It is important to note that RTT and autism, which share some behaviors, are distinct clinical disorders. Through Dr. Zoghbi's work scientists now recognize that RTT is caused by MeCP2 mutations. The link between MeCP2 and autism is likely more complex, in part because what we call autism is probably not a single disorder, but rather a collection of conditions caused by several factors. A key question is why MeCP2 damage may cause RTT in some individuals and autism in others? An educated guess is that multiple factors - genetic, environmental or both - contribute to autism and affect Rett phenotypes, and MeCP2 damage just happens to be a genetic one they have in common. Thus a goal for researchers focusing primarily on autism is now to determine whether MeCP2 is damaged in autistic patients who do not exhibit full-blown RTT.

That question is precisely what the Zoghbi lab is pursuing, and the results look promising. Again using her CAN Genius Award, Dr. Zoghbi and her colleagues have found MeCP2 mutations in the DNA of a few individuals with autism but not RTT, strongly suggesting that direct MeCP2 damage can be a factor in some cases of autism. And in a highly suggestive parallel investigation, a group headed by Dr. Mariko Momoi in Japan has just reported that another protein, known as MBD1, which is related to MeCP2 and also silences DNA, is mutated in an autistic child and the patient's father. We don't yet know if MBD1 has splicing activity like MeCP2. All of these findings lead to a very exciting new proposition: that it is loss of the ability to suppress expression of inappropriate genes (or to splice them) that is common to autism, not the loss of a single specific protein.

Experimental testing of this hypothesis, which was inspired by Dr. Zoghbi's pioneering investigations in 1999, is ongoing in her lab. The focus on silencing and potentially on mRNA splicing is a tremendous stimulus to scientists in the autism field and a reason for great optimism in the autism community as a whole. Dr. Zoghbi reports that since her award from CAN, three new investigators interested exclusively in autism have joined her lab, evidence that such investigations create a snowball effect, attracting greater numbers of molecular and cell biologists to the field, and even larger amounts of funding.

These studies may also suggest a potential new battery of biomarkers - specifically, MeCP2, MBD1, and possibly other genes encoding either "silencing" or "splicing" proteins - that could be used in early diagnosis, which is so critical for targeted and timely intervention. They also highlight that common disease mechanisms may be uncovered more quickly by studying disorders that share autism as a feature. Most importantly, Dr. Zoghbi's work and now that of others in labs worldwide is addressing what goes wrong in autism on the cellular level, so we can begin to devise intelligent cures.


Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. (1999) Rett syndrome is caused by mutations in X-linked MeCP2, encoding methyl-CpG-binding protein 2. Nature Genetics 23, 285-288.

Hamilton SP, Woo JM, Carlson EJ, Ghanem N, Ekker M, Rubenstein JL. (2005) Analysis of four DLX homeobox genes in autistic probands. BMC Genetics 6, 52-63.

Li H, Yamagata T, Mori M, Yasuhara A, Momoi MY. (2005) Mutation analysis of methyl-CpG binding protein family genes in autistic patients. Brain Development 5, 321-325.

Moretti P, Bouwknecht JA, Teague R, Paylor R, Zoghbi HY. (2005) Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome. Human Molecular Genetics 14, 205-220.

Samaco RC, Nagarajan RP, Braunschweig D, LaSalle J. (2004) Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. Human Molecular Genetics 13, 629-639.

Young JI, Hong EP, Castle JC, Crespo-Barreto J, Bowman AB, Rose MF, Kang D, Richman R, Johnson JM, Berget S, Zoghbi HY. (2005) Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc Natl Acad Sci U S A. 102, 17551-17558.