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If you’ve ever wondered why a Rett diagnosis is based on clinical features and not a positive MECP2 test or if you have a child with a Rett diagnosis but no MECP2 mutation or the other way around then this is a video for you. What exactly does atypical Rett mean and should individuals with CDKL5 and FOXG1 mutations be considered Rett? All these topics are covered in the video below.

[video transcript]

by Monica Coenraads

Variations in our genome are what make us unique. It’s also what predisposes or protects us from disease.  For example, you may know people who eat high fat diets and yet have low cholesterol or people who, although they have never smoked, succumb to lung cancer, like Christopher Reeve’s wife, Dana.

I’ve had the opportunity to meet girls with MECP2 mutations and normal X chromosome inactivation that are too high functioning to be diagnosed clinically with Rett Syndrome. These are girls who may walk, run, speak, write, draw, and in some rare instances even speak multiple languages and play an instrument. So what is protecting these individuals from having full-blown Rett?  You guessed it: modifier genes.

Those of you familiar with RSRT’s efforts know that we have been funding a project in the lab of Monica Justice aimed at identifying protective modifiers in mice.  This past summer the Justice lab published the first modifier that suggests that statins (drugs that lower cholesterol) may be treatment options for Rett.   More modifiers are likely to follow.

In the last few years a number of factors have coalesced to make the hunt for modifiers possible in people: 1) the identification of a growing number of individuals with MECP2 mutations who are too high functioning to fit the criteria for a clinical diagnosis of Rett  2) dropping costs for exome sequencing  3) improved bioinformatics which allow for better analysis and interpretation of the vast quantify of data generated from sequencing.

In light of these developments RSRT has awarded $314,000 to Jeffrey Neul at Baylor College of Medicine to sequence the exomes (the protein producing portion of the genome) of high-functioning kids/adults in the hopes that some common variables may point to modifiers which can then become drug targets.

Importantly, the sequencing and phenotypic data will be a valuable resource as it will be deposited into the National Database for Autism Research and available to the scientific community.

We need the Rett community’s help to identify high-functioning individuals who Dr. Neul may not be aware of.
If you think your child may qualify please contact me at

Watch the interview below with Dr. Neul to learn more about this project.

[video transcript]
[video transcript – Chinese]

Monica Justice, Ph.D.

Monica Justice, Ph.D.

Rett Syndrome is a spectrum disorder with a broad range of symptom severity. Some girls can run, have some use of their hands and can speak in short sentences while others cannot even sit or manage to hold their head up. One reason for this variation is the child’s own unique genetic make-up  – in other words, variations in other genes that impact the severity of the Rett mutation. Identification of modifier genes has therefore been a critical component of RSRT’s research program as the modifiers may provide alternate pathways to target.

This hypothesis has now been supported in a major study that could lead to treatments for girls and women with Rett Syndrome.  Today the journal Nature Genetics publishes data on the first reported modifier, called Sqle, an enzyme involved in the cholesterol pathway.

Monica Justice, Ph.D and graduate student Christie Buchovecky from Baylor College of Medicine.

Monica Justice, Ph.D and graduate student Christie Buchovecky from Baylor College of Medicine.

The research was undertaken by Monica Justice, PhD, of Baylor College of Medicine, with a $1.5 million investment from RSRT.  Dr. Justice tested statins (cholesterol-lowering drugs) on Rett mice models with encouraging results.  A human clinical trial is now being planned.

RSRT is committed to seeing this project through to completion as many more modifiers, and therefore druggable pathways,  are likely to be found.  We thank all of our generous supporters and parent organizations who make this important work possible, in particular our funding partners, Rett Syndrome Research Trust UK and the Rett Syndrome Research & Treatment Foundation.


Below are some resources to help you understand today’s announcement.

Press Release
[Spanish Translation]
[Italian Translation]


by Kelly Rae Chi

Rett Syndrome is caused by a variety of mutations in the MeCP2 protein, but in some instances, MeCP2’s end is missing.  A graduate student in Developmental Biology at the Baylor College of Medicine in Houston, Steven Baker, who is also in the medical scientist training program, was sifting through the clinical literature on boys with such mutations when he noticed that a tiny difference in how much of the protein’s tail is shortened—by just three amino acids—seemed to make the difference between decades of life (albeit with Rett-like deficits) and death in infancy.

Steven Baker

Steven Baker

Baker asked his adviser, Huda Zoghbi, whether she thought those extra few amino acids could so dramatically change the clinical progression of Rett.

Huda Zoghbi

Huda Zoghbi

“I don’t know,” Zoghbi, Howard Hughes Medical Institute Investigator and director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, recalls telling him, because other genetic factors could be contributing the dramatic difference in the progression of Rett. “The only way to know is to make mice that have the two different mutations.”

So they did. One mouse had the end of its MeCP2 cut off at the 270 mark (‘R270X’ mice) while another’s protein was shortened at the 273 mark (‘G273X’ mice). The stories of these mice were reminiscent of the boys Baker had noticed. The R270X mice died prematurely, around the same time as mice with no MeCP2. In contrast, the G273X mice, with their extra three amino acids, survived longer and showed symptoms later, although these features became more severe and the mice died before healthy mice did.

What do those amino acids do? In trying to find out, the scientists have refined their understanding of how MeCP2 works. Their results are published this week in Cell.


A first look at DNA binding:

Researchers know that MeCP2 binds throughout the genome, coating the DNA in neurons more heavily than in other cells, but what exactly it does after that is less clear. It’s thought to turn genes on or off, or alter the overall structure of DNA.

Zoghbi’s team thought that the two truncated forms of MeCP2 might bind to DNA differently — in a way that would help explain the different clinical progressions of the boys — but when they initially looked at several spots within the genome they saw that both forms bound to those spots similarly.

In fact, looking more broadly across the genome the group found that overall binding of the MeCP2 was pretty much the same, and it looked normal. (The latter wasn’t too surprising, though, because the front end of MeCP2 was already known to bind to DNA.) Both mutations also interfered with the normal ability of MeCP2 to repress genes.

Looking more closely at gene expression at various time points in brain development, however, the group found a key difference in the two mutants: at 4 weeks of age, a small group of genes was improperly expressed in the R270X mutant but not in the G273X mutant. Interestingly, most of those genes eventually became misregulated in the G273X group by 9 weeks.

The hook from the animal kingdom:

Meanwhile, the scientists asked evolutionary biologist, Olivier Lichtarge, a Professor at Baylor College of Medicine who uses computational tools to study the evolution of protein sequences, to help them compare the sequences of the protein’s tail across different species (the idea being that any regions of the protein that were highly similar across species might be important for the protein’s function). “We worked with Angela Wilkins in the Lichtarge lab and asked, ‘Is there something in this domain that’s really unique?” says Zoghbi, who is also a Professor at Baylor College of Medicine.

They found that three clusters of MeCP2’s tail were highly conserved across fish, frog, rat, mouse, and human. Shortening MeCP2 at the 273 mark removed the third of those conserved clusters, whereas cutting the tail at the 270 mark deleted the second and third clusters.

What are these clusters in MeCP2’s tail and what do they do? It turns out that they’re called AT-hooks. In 2005, a study by Adrian Bird’s group described the first of those three AT-hooks (which is the one still present in both of Zoghbi’s new models), though its function was unclear.

AT-hooks are regions of a protein that are already well known to bind DNA, however, so the team went back to the idea that the two truncated proteins might differ from one another in how they attached to the genome, even though their initial results had shown that binding was similar. Using a different assay, they found that missing the second AT-hook domain impaired the ability of the R270X to steadily interact with certain sequences in the genome.


The interaction between MeCP2 and DNA:

Our genomes are wound tightly around spool-like proteins called histones; the DNA and histones (together, called chromatin, which looks like beads on a string) are then packed in even more so that it can all fit inside cells. Using an experimental model of compaction in vitro, the team found results suggesting that R270X mice (which, remember, are missing an two AT-hooks instead of one) don’t pack up chromatin as well as 273X mice do.

The initial finding that both mutated forms of MeCP2 bind to DNA are still important though, Zoghbi says. “It tells us that the major binding to DNA happens. That’s the first step.” The researchers think that once the front end of MeCP2 sits on DNA, the AT-hook clusters on its tail come in manipulate the DNA further, likely bending or altering the structure to help it pack further into the cell.

“There were hints previously that MeCP2 might cause a change in the overall conformation of DNA. The new study is probably the most direct evidence,” says Howard Hughes Medical Institute Investigator Gail Mandel, at the Oregon Health and Science University in Portland, who was not involved with the study.

The protein partner ATRX:

When the MeCP2 sits on DNA, and likely alters the way it packs into a cell, there are other molecular partners that come and join it. One of those is the protein ATRX—whose mutations have been linked to Alpha-thalassemia mental retardation syndrome—and Adrian Bird’s lab has previously shown that its interaction with DNA is disrupted in mice missing MeCP2. Zoghbi’s team decided to look at this protein in their new mutant mice.

Compared with the healthy mice and the G273X mice, ATRX goes missing from the tightly packed DNA of neurons earlier in life for the R270X mouse, and this loss mirrors the quicker onset of Rett symptoms. “To us, that was really interesting,” Zoghbi says, “because this change is not because the neurons are sick, it’s because you don’t have MeCP2 functioning properly.”

Studying female mutant mice that are missing a copy of MeCP2, the researchers found those brain cells with no MeCP2 also had less ATRX bound to tightly packed DNA compared to controls. In female mutants with too much MeCP2, an excess of ATRX latched on to DNA. MeCP2’s absence from liver and non-brain organs didn’t affect ATRX binding in those organs, suggesting that MeCP2 has a mechanism that’s specific for the brain.

Future directions:

Taken together, these results suggest that in the brain, the AT-hook clusters on MeCP2’s tail are manipulating DNA in a way that’s crucial for the other protein partners to bind and do their jobs, Zoghbi says.

“This new paper is beginning to shed light on the complexity of this interaction between MeCP2 and ATRX,” says Mandel. In addition, “we don’t know all the other proteins that bind to MeCP2, but the guess would be that there are likely more partners affecting whether genes are on or off.”

Zoghbi’s team hopes to understand how shortening MeCP2’s tail changed chromatin structure without dramatically changing gene expression — as well as the mutation’s affect on brain activity. They also plan to do biochemical and molecular experiments to figure out where ATRX is going and what it’s doing when its distribution is altered in the brain cells of the MeCP2 mutants.

For Zoghbi, the new findings underscore the importance of going back to patients to look for clues about MeCP2’s function. In 1999, Zoghbi first showed that various mutations in MeCP2 caused Rett. “Here we are 14 years later, some of these human mutations are teaching us lessons,” she says. “The variety you get and the breadth of human features you can dissect and go back and study in the mouse are really very humbling.”


Last month brought me to Houston, Texas to attend a fascinating meeting organized by Huda Zoghbi and Morgan Sheng and co-sponsored by RSRT. Entitled Disorders of Synaptic Dysfunction, the event was the inaugural symposium of the recently established Jan and Dan Duncan Neurological Research Institute, directed by Dr. Zoghbi.

The two-day meeting brought together a heterogeneous group of scientists from academia (senior and junior faculty as well as post-docs and graduate students), industry, NIH and other funding agencies.

The focus was not on  a single disease but rather on a group of disorders (Rett, Angelman, Fragile X, autism, Tuberous Sclerosis) that share a common cellular phenotype: abnormal synapse activity.

It’s no surprise that some of the talks that generated the most buzz came from labs that are doing very clinically relevant research. These include the labs of Mark Bear at MIT, working on Fragile X, and Ben Philpot at UNC whose lab works on Angelman Syndrome.

Like Rett Syndrome, Fragile X is a single gene disorder, caused by mutations in a gene called Fmr1. When Fmr1 is mutated, protein synthesis fails to shut down, leading to excess. Some years ago Dr. Bear proposed that compounds which can block a certain type of receptor, mGluR5 (which triggers the burst of synaptic protein synthesis) might counteract over-expression of protein and thereby cancel out the damaging effect of Fmr1 deficiency. His theory has proved correct, and clinical trials of mGluR5 antagonists are currently ongoing at multiple pharmaceutical companies.

I first met Dr. Bear almost a decade ago, when he was just beginning to formulate what is now commonly known as the mGluR5 theory of Fragile X.  His lab is currently funded by RSRT to explore protein synthesis in the Rett mouse models. Dr. Bear hypothesizes that Rett may be due to under-expression of proteins. If his hypothesis holds up, pharmacological manipulations of mGluR signaling will be pursued.

Ben Philpot’s talk also generated excitement. He discussed a high-throughput screen that has yielded a compound which can activate the silenced Angelman Syndrome gene, UBE3A. Dr. Philpot is currently funded by RSRT to pursue a similar approach for the silent MECP2 gene on the inactive X chromosome.

Mike Greenberg spoke about MECP2 and shared unpublished data that has come about from his collaboration with Adrian Bird via the RSRT funded MECP2 Consortium. (More on that in the months to come.)

Jackie Crawley of the NIH gave a brilliant talk on how “autistic mice” are being characterized to yield a plethora of new information.  For me the highlight of her talk was hearing recordings of mouse “speech”. She shared a variety recordings and I was taken aback by the complexity and richness of the sounds, which left me yearning for an analysis of Rett mouse vocalizations.

After a lively cocktail hour it was back to work with dinner plates in hand. Drs. Zoghbi and Sheng divided the attendees into three working groups: 1) dysfunction of proteins of the synapse 2) dysfunction of nuclear/cytoplasmic proteins 3) young investigators and junior faculty.  Masquerading as a 30-something I happily joined the third group.  I was struck by the fearlessness and boldness of these young scientists. There were not shy about criticizing the status quo and what could be done differently to enhance the research progress. I came away feeling buoyed and reassured that science is in good hands with this new generation.

The following several hours of discussion, led by Rodney Samaco and Mingshan Xue and facilitated by NIMH Director, Tom Insel, were intellectually stimulating and entertaining. Below is a visual output of our intense discussion.

A few personal reflections on the symposium

  • Over and over again throughout the meeting I heard comments from autism researchers such as: “Where would we be without the syndromic autism animal models like Rett and Fragile X? We’ve learned so much from them”.  More than once I found myself thinking that as horrible as Rett is at least the genetics of the disorder are clear-cut – Rett’s silver lining.
  • The meeting provided an opportunity to meet some scientists with whom I had communicated by email and/or phone, but never met in person. People like Pat Levitt, Freda Miller and Michael Palfreyman.  It was a reminder of how many people over the years have taken the time to discuss their work and possible synergies to Rett Syndrome.
  • Drs. Zoghbi and Sheng kept everyone busy from the moment the meeting started to the moment we left, including an intense working dinner. I tend to do the same thing  at meetings that I organize, but always feel like I’m being a bit of a slave driver. Never again, however, will I feel guilty. If Dr. Zoghbi thinks it’s acceptable, then so do I!

Kudos to Drs. Zoghbi and Sheng for a stimulating meeting and thank you both for inviting me.

Science Translational Medicine, which co-organized the meeting, will be publishing a white paper on the proceedings.
RSRT will let you know when the paper is available.

Monica Justice, Ph.D. – Baylor College of Medicine

By Monica Coenraads

Last week the trustees of RSRT voted to award continued funding to Monica Justice of Baylor College of Medicine.  Dr. Justice is a mouse geneticist (yes…there really is such a thing) who is spearheading one of the most unique projects in the Rett research arena today. For background information please read the September 2009 blog interview with Dr. Justice.

This project is a mammoth undertaking – the kind that requires a certain sense of fearlessness on the part of the investigator (and the funding agency). The risks are high but are in line with the potential rewards.

I feel a certain sense of attachment to this particular project as I was present when the idea was first suggested. At the time I was the Director of Research at the Rett Syndrome Research Foundation (RSRF) and I organized the annual Rett Syndrome Symposiums that spanned three days at the end of every June. At the 2006 meeting I cajoled two dozen of the brightest and most creative scientists to join me for an early morning, pre-meeting gathering I called the “knowledge gap meeting”.  I posed the following challenge: develop a prioritized list of high-impact experiments that no one was currently undertaking and that was unlikely to be funded by traditional agencies. After a two-hour discussion the group delivered their top contender: a modifier screen to identify genes that suppress the effects of an MECP2 mutation.

My next task was to find the best possible person to undertake the screen and talk them into taking it on.  I organized a Rett workshop a few months later at a “Mouse Genetics Meeting” (yes…they have those) in Charleston, SC, which attracted a number of candidates.  Bottom line – I courted Dr. Justice and she enthusiastically agreed to pursue the project.

Fast-forward almost five years and I’m delighted that the project is thriving and yielding a wealth of information. I recently caught up with Dr. Justice to discuss how the project is faring.

MC:  Dr. Justice, thank you for taking time away from your work to bring our readers up to date on your fascinating project.  Please tell us how things are going.

MJ:  My pleasure, Monica. I want to start by saying that this project would never have been funded by the NIH [editor’s note: National Institutes of Health] nor would I have proposed this to your foundation, had you not approached me about it.  I knew little about Rett Syndrome when I started this project.

MC:  Tell us a bit about modifiers. Do you think they exist for every disease?

MJ:  I think that most diseases can be influenced by mutations but I don’t think every disease necessarily has modifiers.

MC:  Do you have a sense of how many screens like yours are ongoing right now?

MJ: I know of only a few in the mouse.

MC:  Do you know of any screens that have yielded modifiers that suggest a drug for the particular disease?

MJ:   That’s a great question, Monica. I do not. The goal of most of the modifier screens is not to identify drugs but rather to understand some developmental or biochemical pathway. I think with our screen we are learning a lot about the biology of the pathway, but our hope is to find a drug-targetable pathway.

MC:  Can you summarize the progress and the ups and downs of the project?

MJ:  At the inception of the project we encountered several problems. We really had no idea that the Mecp2 mutant females would be such poor breeders. We tried all sorts of tricks to improve their breeding capacity, because we needed a lot of them to do the screen, and nothing worked.  We kept at it, though, just with basic mouse breeding, and eventually got up to speed. Also, in the beginning we had some communication issues within the lab. I’m not sure we were expecting quite as many modifiers as we found. But we then developed a system, and that system worked very well; then things started moving along beautifully. I also realized early on that I needed to participate in a very hands-on way with this project.

As we isolated each modifier line, we realized that each one was different: that is, none suppressed the disease entirely, but each modifier line appeared to suppress a subset of Rett symptoms.  Even so, each line allowed the mice to live longer, function better and be healthier. However some of them developed other symptoms, such as inflammation and susceptibility to infection, which could also shorten their lifespan.  So, we worked with our veterinarians who helped us decide how to treat these mice. For example, we found that putting them on antibiotics worked extremely well.

And so, there were some unforeseen glitches in the beginning that are moving very smoothly now. We have isolated five modifier lines. We have put the screen on hold for now and are concentrating on understanding these five modifier lines. We have identified three suppressor genes so far and have candidates for the other two.  We feel that the screen and the gene identification have gone extremely well. Each of the modifiers has a different phenotype in that they rescue different symptoms, and we find that each modifier locus is affecting a different gene.  For example, in one line that we named “Romeo,” the suppressor delays the onset of Rett-like symptoms, and the mice have no inflammatory lesions, but eventually, the mice succumb with symptoms.  Therefore, the onset of neurological symptoms is later in their life, making their lifespan longer.  Another line, “Henry” develops almost no Rett-like symptoms, and lives nearly a full long life, with only a few mild inflammatory skin lesions late in life.  Another line, “Cletus”, rescues some of the neurological symptoms so the mice live longer, but the long-lived mice have severe inflammatory lesions, even early in life.  Remember that each of these lines carries the Mecp2 (Bird) null allele, along with a second site mutation that alleviates its symptoms.

MC:  It’s possible to figure out statistically how many mice you have to go through so that you’ve saturated the genome – in other words, ensure that you have a mutation in every gene. What percentage of the genome has your screen hit so far?

MJ:  I think we are between ten and twenty percent of the way through.

MC:  So there is a way to go.

MJ:  Based on our work thus far we could find another 25 modifiers.

MC:  The ideal situation is that the suppressors you find are in pathways that are somewhat known and, ideally, for which there are already drugs associated. But you also have to figure out just how the suppressor inhibits the ill effects of having an MeCP2 mutation.

MJ:  Yes, there are many steps that we have to take after we find a modifier gene, to understand what’s going on.

MC:  One of the surprising things that have already come out of your screen is the mere fact that MeCP2 has so many modifiers. Why do you think that is the case?

MJ:  My hypothesis is that the biological system in Rett is sort of poised on the edge, and it’s not so detrimental that it, for instance, causes death immediately. It’s very easy to tip the scale toward a little bit better—– or a little bit worse.  And my feeling after doing the screens is that MeCP2 creates that kind of situation in the cells, that they’re poised to go one direction or another pretty easily.

MC:  Your hypothesis suggests that there could be lots of things that improve Rett symptoms.

MJ:  Absolutely. And maybe combining them will provide an amazing improvement.

MC:  What is your time frame for restarting the screen?

MJ:  I’m usually an optimist about time; my hope would be that, within a year, we could start the screen again.

MC:  One of my favorite things about the screen is that it is completely unbiased. Preconceptions and favored hypothesis don’t play a role here. The animal tells you what is important and you simply go where the data leads you. I find that very reassuring.

MJ:  I completely agree.  Often, we have been totally surprised, then after generating more data, the mode of suppression makes complete sense.  We are learning a lot from these animals.

MC:  I will leave our readers with one last comment.  Over the past 12 years I’ve overseen peer-review for well over a thousand research applications for funding. So I’ve read my fair share of reviewer comments. Typically reviewers are a conservative bunch; even if they are enthusiastic about a project they tend to be cautious. Your recent proposal, however, generated comments like  “Wow”. That’s truly unusual and a real tribute to your creativity, risk-taking and perseverance. I am thrilled that RSRT can partner with you and hope that together we can deliver some much-needed treatments to kids and adults who are in such desperate need.


by Monica Coenraads

Last week I attended a scientific meeting held in Stresa, Italy and organized by a parent group, Pro Rett Ricerca. One of the most well received talks of the speaking program was presented by Monica Justice, PhD of Baylor College of Medicine, who discussed data collected from her RSRT-funded project. What follows is an excerpt from a recent conversation between the two Monicas following the Italian meeting.

Justice mj-qt5

MC: Dr. Justice, it was great to see you in Italy. I thought it might be helpful to give our readers some insight into your project. But first I’d like to start with you, the soul behind this impressive undertaking. How did you end up in science?

MJ: My grandfather was a vet and I had an uncle who was a physician. I have always had a deep love for animals so as a child and young adult I wanted to be a vet.  My father thought that was not an appropriate career for a woman and he and my uncle encouraged me towards the medical field. Early on, however, I realized that my true passion was in basic research.  I went to graduate school thinking I would focus on immunology and microbiology but my very first class would change my career path forever. My professor was switching into the mouse genetics field and invited me to join his lab.  I loved mouse genetics from the very start and knew immediately this was exactly where I wanted to be.

MC: Most lay readers of this blog will not have realized that mouse genetics as a field exists.  Can you elaborate on this specialty?

MJ: When I entered the field most mouse genetics was being carried out in a few labs, The Jackson Laboratories being the primary one in the US, and research centered around a few mouse mutations that primarily altered mouse coat color.  I think the perception from the science community at large was that we weren’t doing particularly important work. That perception changed with the introduction of very powerful research tools.   One such tool was the ability to alter genes in mouse embryonic stem cells to engineer DNA mutations at will. The second was the ability to use a strong mutagen, called N-ethyl-N-nitrosurea or ENU, to do forward genetics – more on that later. This was also the time when molecular biology was exploding.  Rather quickly the mouse became THE model organism of choice. I’ve ridden that wave since my graduate student days. Today nearly every institution that is doing cutting edge research has a mouse genetics core.  I suspect there are now about 2000 true mouse geneticists worldwide.  Nearly every person who works on human disease now works with mouse models.

MC: Please tell our readers the basics behind your Rett project.

MJ: Our Rett project is based on two discoveries:  1) that you could make the symptoms of Mecp2 mutant mice better if you  introduced brain derived neurotrophic factor (BDNF) and 2) Adrian Bird’s  finding that you could actually reverse very severe symptoms in the mice by reintroducing the gene. Because of those two findings I believe that Rett symptoms can be altered by other genetic mutations. I felt strongly that the genetic approach that I was familiar with would be an ideal strategy to try and identify suppressors of the symptoms of Mecp2 knockout (ko) mice.

So let me tell you a bit about the screen. I use a powerful mutagen, ENU, that induces mutations in mouse sperm at a very high rate. We give the mutagen to wildtype (normal) male mice and then mate them to female Mecp2 knockout mice. A certain percentage of their offspring will have no Mecp2 and a sporadic mutation somewhere in their genome.  We then analyze the mice very closely and look for any that appear healthier than your typical Mecp2 ko mouse.  For example, a Mecp2 male ko mouse is dead by 6-14 weeks. If a mouse in our screen lives much longer than that, we hypothesize that there is a mutation in another gene that suppresses the ill effects of having no Mecp2. We currently have mice that are over a year old and still do not show signs of Rett.

MC: How many mice has your project generated?

MJ: We have used about 10,000 mice at this point and envision needing 5,000 more to find and understand the current genes of interest. To reach saturation for our screen, meaning that we are confident that the mutagen has generated mutations in every gene that could potentially be a suppressor, we would need to screen through five times the number of males that we have done thus far. Statistically, I estimate that there are 25-50 suppressor genes that we would expect to find were we to hit saturation.

MC: What kind of precedents are there for success using ENU modifier screens?

MJ: The first successful modifier screens were done in bacteria and yeast. The technique gained momentum in the late 1980’s early 1990’s when Gerry Rubin carried out a modifier screen in the fruit fly for genes that would interfere with a particular pathway. Dr. Rubin is a famous scientist who now is the Director of the Howard Hughes Medical Institute Janelia Farm Research Campus.   Historically, people thought that fruit flies were the only organism that you could do this with. It’s clear now that the mouse is an equally powerful organism.  My graduate mentor, Vernon Bode, did a screen in mice for PKU modifiers, which was finished by Bill Dove at the University of Wisconsin Madison.  And an Australian group that works on diseases of the blood did an ENU mouse screen looking for genes that influence platelet counts.   Each of these screens was very successful.

MC: Is there data to show that modifier genes are the rule or the exception in disease?

MJ: That’s a very interesting question. I work in the Department of Human and Molecular Genetics at Baylor. What I see from many of my colleagues’ work is that genetic modification of disease is the rule and not the exception.

MC: Can you envision a situation where you find modifiers in the Mecp2 ko mice but those genes are not implicated in the human disorder?

MJ: I do not think that we will find modifiers that are mouse specific only. I believe that because the mouse model for Rett Syndrome is amazingly similar to the human disease.  Also, DNA methylation (which is critical to MECP2) and some of the possible functions of the MECP2 gene are highly conserved between species. So it’s very likely that the MECP2 gene in people and in mice is doing the same thing.


MC: What do you foresee as the best possible outcome?

MJ: I foresee finding a molecule that would help forge neuronal connections, and help these connections be maintained and molded.
Furthermore, whatever molecules we find that suppress Rett symptoms may also give us important biochemical information on other genes that may interact with Mecp2.

MC: Did being at Baylor, a Rett hotspot, impact your decision of taking on this Rett project?

MJ: I have been very much aware of Rett since I moved to Baylor in 1998, a year before Huda Zoghbi identified the gene. I have been on the student committee of some of Dr. Zoghbi’s students, which kept me up- to- date on the ongoing work. MECP2 is a transcription factor and I’ve always been interested in transcriptional regulation. What really brought me into the project was when you called me up with a proposition.

MC: When I was the Director of Research at the Rett Syndrome Research Foundation (several years before the merger with IRSA to form IRSF) I piggybacked an early morning think tank during the RSRF Rett Syndrome Symposium in Chicago. About two dozen creative thinkers were kind enough to drag themselves out of bed and brainstorm with me about potential key experiments that could significantly move the field forward.  At the top of that list was an ENU mouse modifier screen. The group also gave me a list of potential people who could undertake such a laborious and intense project…it was a small list and your name was on it.  As you well know, RSRF then organized a workshop at the Mouse Genetics meeting, which took place in Charleston, SC in 2006. Those discussions led to the funding of your project.

MJ: I was so thrilled when you called. There was a time when I would have turned down this project.  But the timing of your call was perfect. The project appealed to me very strongly as a geneticist but also as a compassionate person who wants to make a difference in the life of others.

Your readers should also know that this is a project that the NIH would never have funded.  It was too risky and too “out there”.  I knew this was a viable technique and I was confident with the expertise of my lab with regards to mouse breeding, husbandry and handling that would move this project along quickly so I am very grateful to have had the funding to pursue this.   People should be aware of how much private foundations such as RSRT move the field forward by funding high risk, but high impact projects.

MC: Speaking of compassionate person, at the end of your talk in Italy you got a little emotional.  I was quite touched by that. Can you tell our readers what was going through your mind?

MJ: Yes, I got a little “verklempt” and I got teased quite a bit at dinner for that. I take this project very seriously because I feel that what we are doing could have an impact on people’s lives – an impact that perhaps wouldn’t happen without the screen – I guess as I was up there in front of scientists and the organizers of this meeting who have children suffering from Rett – the importance of our efforts hit me hard.

MC: Are you able to give our readers a hint at the data that your project has thus far yielded?

MJ: The project is at an exciting point.  We are close to identifying our first suppressor gene and we have a few more potential genes that we are pursuing as well.  Once they are identified we will begin experiments to confirm that they are indeed interacting with Mecp2m, first in the mice and then in people.  I also think the modifiers we have so far are just the tip of the iceberg.  So we have a lot more screening ahead of us.

I love this project, it’s fun, it’s exciting, and each new piece of data that we identify brings us closer to our goal.

MC: On behalf of families everywhere who love a child with Rett Syndrome we wish you Godspeed. We look forward to hearing about future progress.  Thank you also to Pro Rett Ricerca and especially Rita Negri and Laura Rassetti for their tireless work to organize this meeting.

MJ: It was my pleasure and honor to attend the meeting in this most beautiful area of Italy, near where you were born.


Our inaugural post includes interviews with Huda Zoghbi, M.D. and Adrian Bird, Ph.D. — two people whose names have become almost synonymous with Rett Syndrome.   It was due to Dr. Zoghbi’s tenacity and commitment that the Rett gene, MECP2, was identified in her lab in 1999. After seeing her first Rett patient in 1983 she became determined to find the disorder’s genetic cause. It took 16 years of hard work and determination.  Dr. Zoghbi’s efforts ushered in the appearance of Professor Adrian Bird.  He had discovered the MeCP2 protein earlier that same decade, years before anyone knew it was related to a human disease. During this decade they have both made many key contributions to the Rett field. Rett Syndrome is high-profile disorder in the neuroscience community, in large part, due to their efforts.  They play a key role at RSRT as trustee and advisors.



Huda Zoghbi, M.D. is an internationally renowned physician-scientist at Baylor College of Medicine and an investigator of the Howard Hughes Medical Institute. Click here for the first part of a two-part interview.



Adrian Bird, Ph.D. is the world’s leading expert in the gene MECP2.  He is the Buchanan Professor of Genetics at the University of Edinburgh and the Deputy Chair of the Wellcome TrustClick here to read his interview.