You are currently browsing the monthly archive for February 2010.
[SPANISH] Redefiniendo la Función de la Proteína del Síndrome de Rett
[ITALIAN] Ridefinire le Funzioni della Proteina Chiave della Sindrome di Rett
Just before the holidays I had an opportunity to discuss with Adrian Bird the new data reported in his latest paper, published today in Molecular Cell. Most readers of this blog will know that Prof. Bird discovered the MeCP2 protein in the early 1990s while working at the Research Institute for Molecular Pathology in Vienna. Almost a decade later, Huda Zoghbi’s finding that mutations in MeCP2 cause Rett Syndrome propelled Prof. Bird into the realm of neuroscience. He found himself working, for the first time, on scientific issues with great relevance to human disease. In 2007 he published the dramatic reversal experiments.
We’ve come to expect novel and significant insights from the Bird lab; this new paper redefines our concept of both the scope and function of MeCP2. In the words of co-author Peter Skene, it may be “the watchdog of the neuronal genome.”
MeCP2 Goes Global
MC: I found the data in your latest paper regarding the high levels and broad distribution of MeCP2 to be quite striking.
AB: Yes, MeCP2 is exceptionally abundant. Most transcription factors, proteins that turn genes on or off, exist in 10,000 to at most 100,000 molecules per cell. We are seeing 100 to 1,000 times more than that of MeCP2. In fact, there is almost as much MeCP2 in the nucleus as there are nucleosomes, which are the fundamental repeating structural units of chromatin. That means that there is enough MeCP2 to potentially cover nearly all of the genome.
MC: I was intrigued by the fact that MeCP2 binds to non-genes as well as genes.
AB: As far as MeCP2 is concerned it doesn’t seem to care whether it binds to genes or not. It simply binds everywhere there are methyl groups.
MC: So MeCP2 follows methylation across the genome.
AB: Indeed, and this tracking of DNA methylation could explain the reversibility of severe Rett symptoms that we see in mice. The important developmental step is to establish the correct pattern of methylation, and that appears to happen normally in Rett patients. Once you have that pattern set down, and you put MeCP2 back in, as we did in our reversal experiment, the protein simply goes where it’s told by methylation and resumes its function.
The Genome – It’s Not All About Genes
MC: This is probably a good time to remind our readers that only 5% of the genome is made up of genes. The rest comprises what is still sometimes referred to as “junk DNA” because scientists have not been able to ascribe any function to it. I’ve always found the term “junk DNA” a bit arrogant – I doubt that 95% of our genome is junk and in fact recent work has suggested that the junk might in fact have important regulatory functions.
AB: You are absolutely right; we shouldn’t dismiss any of the genome as junk. Much of this so- called “junk DNA” has actually been conserved over many millions of years and that fact alone suggests that there is a good reason for that “junk” to be there.
MC: In recent years the idea that MeCP2 binds to methylated DNA has been questioned a bit. This paper reaffirms and expands on that. Where is this leading us?
AB: I think this confirmation, combined with an abundance of MeCP2 sufficient to cover all the methyl groups in the genome, is telling us something about the function of MeCP2.
MC: So can we still say that Rett symptoms are caused by faulty repression of downstream genes by MeCP2?
AB: That remains a hypothesis that needs proving. We are still waiting for evidence that particular genes, when misexpressed due to mutated MeCP2, are causing Rett. We have a lot of work yet to do to figure out the connection between the absence of repression by MeCP2 and the symptoms of Rett.
MC: So what about the papers that claim particular genes are targets of MeCP2?
AB: Indeed, there have been quite a lot of papers – some written by our lab- which say that certain genes appear to be changed when MeCP2 is missing. The finding is followed up with biochemistry experiments which show that MeCP2 binds to these genes, so the data seems to make sense. However, once you find that MeCP2 binds absolutely everywhere, the concept of target genes becomes a bit less interesting and perhaps less relevant.
MC: If MeCP2 is not a transcription factor, as previously thought, what would you call it?
AB: I would call it an alternative linker histone 1. Ages ago we showed that MeCP2 and the linker histone, HI, compete with each other to assemble chromatin on methylated DNA. In this paper we show that when MeCP2 is absent, the amounts of HI, which are normally very low in the brain, go up dramatically. In that sense MeCP2 clearly resembles a histone.
MC: Let’s give a bit of background for our readers. Histones are proteins which act as spools around which DNA is wound. This winding, or compaction, allows the 1.8 meters of DNA material to fit inside each of our cells. There are two classes of histones – core histones and linker histones. Core histones form the spool around which DNA winds – resembling beads on a string. And linker histones are the DNA separating the beads. HI is one of two linker histones. So, in effect, linker histone is the string between the beads of a necklace.
Might It Be Simpler?
MC: Yet another observation of your paper is that MeCP2 is likely performing the same function throughout the brain. Please elaborate.
AB: Some think that MeCP2 does different things in different neurons. Our data suggests that the pattern of MeCP2 binding is similar regardless of the brain region. My emphasis has turned to the idea that, in the absence of MeCP2, there is a generic problem with neurons and that the regional effects have something to do with what those neurons do in the brain and not so much that MeCP2 does different things in different places. In other words, MeCP2 does the same thing everywhere but its consequences are different.
Currently there is a lot of data from many labs pulling us in multiple directions. I would like to see if we can slice through all that complexity and say, in all these neurons this is what is wrong. I’m excited about the possibility that perhaps it’s not that complicated after all.
MC: That would be an elegant and welcome scenario. Thank you, Prof. Bird, for discussing your latest paper. I look forward to bringing our readers an update soon regarding your work.
As many parents may already know, the Diagnostic and Statistical Manual of Mental Disorders, known as the DSM, is in the process of reevaluating criteria for the new edition to be published in 2013, the DSM V. There is discussion among members of the Rett community and the Asperger’s community about the decisions to drop both diagnoses from the manual. How this change might impact services, particularly intensive educational intervention for Rett children, is unknown and will probably vary from state to state. People who would like to express their opinions to the DSM committee may do so until April 20, 2010.
RSRT scientific advisory board member and Rett Syndrome researcher Huda Zoghbi , M.D. discusses the DSM reclassification with Monica Coenraads.
Huda Zoghbi will be appearing on the Charlie Rose Show on Tuesday, February 23. The episode, entitled “The Developing Brain” is part of the “Charlie Rose Brain Series” hosted jointly with Nobel Laureate, Eric Kandel, Ph.D. of Columbia University.
MC: What do you think was the impetus behind removing Rett Syndrome from the DSM?
HZ: My understanding is Rett was originally included in the DSM because it was a disorder with autistic features of an unknown cause. Now that the genetic cause has been identified, the rationale for removing Rett is that it is more its own distinct entity. Another reason pertains to the transient nature of autism features in Rett patients but this is not exactly the case. Rett patients do not have language skills and continue to manifest stereotyped behaviors for decades. Although some might acquire some social interaction skills through eye-pointing this is not true for all cases.
MC: Yet, if knowing the genetic cause of a disorder is the rationale for exclusion, in time, as more genetic underpinnings of disease are identified there will be fewer and fewer left for categorization by the DSM.
HZ: Correct. That is why I actually do not agree with this approach. I think the approach should be to see what clinically fulfills criteria for autism. I would be in favor of a more precise categorization and dividing DSM V into two types: DSM V A and B. One would be used for syndromic autism and one would be non-syndromic autism. There would be genetic etiologies for both syndromic and non-syndromic. Currently most of the known genetic causes are for syndromic autism but in time, as we do more sophisticated sequencing and we study patients with simplex autism (one case in a family, with no features other than classic autism) we will find etiologies for non-syndromic as well. In my view this would be a much more useful distinction. Bottom-line: having a known genetic cause should not eliminate a disorder from DSM V.
MC: The decision to remove disorders identified with a genetic cause seems very black and white to me. While knowing the root cause of a disorder is hugely important it often also brings many unanswered questions. Let’s look at Rett Syndrome itself – a certain percentage of girls/women with a clinical diagnosis of Rett do not have an identified mutation. And then we have individuals with MECP2 mutations who do not have Rett Syndrome symptoms. So, using Rett as an example of a genetic disorder, the situation is certainly not black and white.
HZ: Absolutely. In fact, the girls who have MECP2 mutations who fit the clinical criteria for autism and do not have Rett symptoms make a very compelling case against the current draft of DSM V. They represent a troubling scenario for an important patient population – what diagnosis do we give them? Where do they belong? So now with the proposed DSM criteria we have a category of patients that are left unattended to in this manual.
MC: It seems to me that the Rett clinical community, in general, was in favor of removing Rett. Do you have any insight into their reasoning?
HZ: The medical community appropriately focuses on clinical management: what treatments can be delivered to the patient, what code is used in the medical records for billing purposes, etc. These issues have probably driven the support of the clinical community for removal. On the other hand, if you are about solving the puzzle of these brain disorders and understanding the pathogenesis of the autism phenotype in Rett and beyond, then removal doesn’t make much sense to me. If you believe that the DSM manual is a tool to help us better understand brain diseases and to highlight the commonalities and differences between them, then I don’t feel taking out Rett serves the cause of disease-oriented research.
MC: Once DSM V is finalized will we be able to call Rett an autism spectrum disorder or will that be a misnomer?
HZ: I don’t think it will be a misnomer because clinically Rett is an autism spectrum disorder. Just because it’s taken out of a manual does not change the phenotype of the disorder. Imagine, for a moment, a girl comes to see me in the clinic. She used to speak but has experienced a loss of language, she has no social interactions, she has stereotypic behaviors. We evaluate her using ADOS (The Autism Diagnostic Observation Schedule – a standardized protocol for assessing social and communicative behavior) and the ADIR (Autism Diagnostic Interview-Revised) and the child fulfills all the criteria for an autism diagnosis. Yet she has a MECP2 mutation. What do you put in her chart? It can’t say MECP2 mutation because that is not a clinical diagnosis, it’s a genetic one.
MC: Of course we are already facing these complicated issues. And I think the proposed changes in the DSM may further complicate things. As you can imagine, I’ve received a plethora of emails and phone calls from parents who are wondering what this may mean for their child in terms of losing services. I think worries about losing medical services are probably not warranted. Worries about educational services, however, I’m much more concerned about. For example, it may become more difficult to obtain intensive ABA (applied behavioral analysis) programs and other educational supports where autism has blazed a trail.
HZ: Yes, I would agree with that prediction. It is really important to remember that autism spectrum disorders do not only overlap clinically but that some of their features respond to similar therapies in spite of different molecular causes. Therefore keeping an eye on the clinical similarities in face of genetic heterogeneity is one path to gain insight about the mechanisms underlying their common features and to develop therapies that might benefit more than one disease. I do hope the committee will take these far-reaching ramifications into account as they contemplate disease classifications.
MC: Thank you so much for sharing these thoughts with our readers. Parents and other advocates for those with Rett Syndrome, such as therapists, teachers or personal physicians, are encouraged to weigh in on this matter. Remember, the cut-off date for submitting comments to the committee is April 20.
CLICK HERE TO WATCH VIDEO
(located half way down the page)