New Epigenetic Player Implicated in Mental Retardation and Facial Birth Defects

The study, published online July 11 in the journal Nature, reveals that this enzyme is a histone demethylase and works with a key genetic partner to help keep neuronal cells alive during development of the embryonic brain. Patients with this form of mental retardation are known to have mutations in the gene that encodes the active part of this enzyme. The findings may help scientists further understand the underlying biological reasons why X-linked disorders cause cognitive impairment and develop new therapies to treat or prevent them.

"Human genetics has made great strides in identifying genes as potential causes of diseases and disorders, but we don't know much about how they work," says senior author Yang Shi, PhD, the Merton Bernfield Professor of Neonatology in the Newborn Medicine division at Children's. "We knew this was a biologically relevant gene. We wanted to understand the etiology, so we asked why the gene causes problems when it is mutated. Here, we have identified a direct target in neuronal and craniofacial development."

The fast-moving young field known as epigenetics is revealing the dynamic structures and processes that organize, index and control access to the information stored in the DNA code. The epigenetic program orchestrates different combinations of gene activity -- allowing cells with identical genomes to be transformed into more than 200 different specialized tissues and organs in our bodies.

When most people think of DNA, they picture the iconic spiraling ladder of naked DNA. But in nature, the twisting double-helix strands actually spool around clusters of proteins called histones with protruding "tails" that act like specialized antennas, transmitting directions for DNA. This dynamic structure, called chromatin, extends the genetic code by offering, measuring or limiting access to different genes.

Several years ago, Shi and his colleagues identified the first enzyme that can detach a molecule known as a methyl group, previously thought to be a permanent fixture, from the histones tails. Then his team and a number of other research groups independently discovered members of a second known family of these enzymes, known collectively as histone demethylases.

The latest study began with a gene mutated in several male patients with X-linked mental retardation and craniofacial abnormalities. The gene codes for an enzyme that looked a lot like a member of the second family of histone demethylases. The mutations in these patients abolished the working part of the enzyme that plucks the methyl group from the histone tail.

Led by Hank Qi, PhD, co-first author and postdoctoral fellow, the researchers demonstrated in human cells that the enzyme, PHF8, indeed works as a histone demethylase. (And it is the first known demethylase discovered for a strategic methylation point on the tail of histone 4 known as H4K20, which other evidence suggests plays a critical role in gene expression and regulation and in the DNA damage response.) In this case, by removing the methyl group, the enzyme appears to maintain active gene transcription.

"The histone methylation and demethylation doesn't turn the gene on or off," Qi says. "When this histone mark changes, it generates an equilibrium important for fine-tuning gene expression."

Despite its widespread presence, the enzyme seems to have a narrowly targeted biological effect on a master genetic regulator of craniofacial development, the transcription factor MSX1. Taking a cue from the scientific literature, Qi and his collaborators, Madathia Sarkissian and Thomas Roberts at Dana-Farber Cancer Institute, tested the normal enzyme function in zebrafish, a popular model for genetic function.

It is hard to judge cognitive impairment in a small fish, but the dramatic impact on craniofacial development was obvious. Fish without the enzyme developed virtually no jawbone, a condition that could be prevented by providing the functioning enzyme, showing its importance in development. As importantly, providing more of the fish version of the MSX1 gene (whose activity the demethylase enzyme encourages) also partially prevented the biological defects caused by the missing enzyme.

Hope for the reversibility of some aspects of mental retardation arose three years ago in a Scottish mouse study of Rett syndrome, a disorder on the autism spectrum that is also a cause of severe mental retardation in girls. The disease is caused by a molecule, MeCP2, that binds to methylated DNA and may be involved in another form of epigenetic regulation.

"In practical terms, we use gene expression as a read out," says Shi, also a professor of pathology at Harvard Medical School. "Epigenetic states affect the expression of critical genes. These studies suggest that the imbalance of histone methylation dynamics plays a critical role in mental retardation. You can imagine a therapeutic approach to enhance the compromised enzymatic activity or to restore the downstream function."

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Children's Hospital Boston.

Journal Reference:

1. Hank H. Qi, Madathia Sarkissian, Gang-Qing Hu, Zhibin Wang, Arindam Bhattacharjee, D. Benjamin Gordon, Michelle Gonzales, Fei Lan, Pat P. Ongusaha, Maite Huarte, Nasser K. Yaghi, Huijun Lim, Benjamin A. Garcia, Leonardo Brizuela, Keji Zhao, Thomas M. Roberts & Yang Shi. Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature, 2010; DOI: 10.1038/nature09261

source: ScienceDaily

Unconventional Transcriptional Response to Environmental Enrichment in a Mouse Model of Rett Syndrome

A very recent and interesting article by Dr. Bredford Kerr and his Team.


Source: Pubmed Central

Clinical Trials on Rett Syndrome

Note: Click on the title to see the page

Source: Clinicaltrials.gov

Vote to 'refresh' research on Rett Syndrome

Although Rett Syndrome is one of thousands of genetic disorders, it is one of four that was able to be reversed in a lab. In 2007, researchers found a way to reverse it in lab mice, giving hope to many, such as the Nues family of Danville, whose daughter Katie was diagnosed in 2003. Yet, without funding, research to safely replicate it in humans needs more research. This is why Paige Nues is hoping to win a $250,000 grant through the Pepsi Refresh Everything project.

Rett Syndrome is a developmental disorder that affects mostly girls and is realized in infancy. While born normal, symptoms begin to appear anywhere from six months to two years after birth. Eventually, the girls lose the ability to walk, speak and use their hands. Other symptoms include seizures; digestive, heart, breathing and circulation problems; and sometimes scoliosis.

According to Paige Nues, Katie is one of three girls in Danville with the disorder, as well as one of dozens in the Bay Area and one of 400 in California.

A diagnosis will likely mean a lifetime of therapies and while these girls usually live into late adulthood, they aren't capable of independent living.

"It is the most severe form of an Autism Spectrum Disorder, but what is different for our girls, is that for the most part, despite their handicaps, they are incredibly happy and social people," Paige Nues said.

The same is true for Katie Nues, who was diagnosed at 12 months and turns 8 on Sunday, July 25.

"On a day when she's feels well, and is not having seizures or stomach problems, she's bright and extroverted," Paige Nues said. "She loves being around typical kids and being in the community."

Katie is the first of three girls for Paige and her husband Jesse. The impact of the disease on the family has been huge. In order to keep up with therapy appointments and care for Katie, Paige made the difficult decision to stop working.

"It was emotionally devastating," she said. "We had what we thought was the perfect child. We thought we had done all the right things. We met, fell in love and prepared emotionally and financially to start a family. You never think it will go wrong."

Yet, even with the diagnosis, Katie is fairly strong and healthy and has a good relationship with sisters, Melissa, 4, and Abby, 2.

"They don't know her any other way, she's just their big sister," Paige Nues said. "But they definitely know she needs extra help."

One day, Paige recalls, they were headed out for a walk in the neighborhood and Melissa was starting to ride a bike with training wheels. Someone said that Katie couldn't ride a bike, but Melissa said, "Yes she can, she just needs our help." And she can, since Katie has a specialty bike just for her.

While Paige said they try not to put extra responsibilities on the other girls, she said Melissa and Abby "have amazing wisdom and sensitivity about (Katie) already."

The Nues family has been working hard to raise awareness and funds for Rett Syndrome research, so it's only fitting that they are doing all they can to get the word out about the Pepsi Refresh Everything grant. Everywhere they go, whether it they go to the grocery store or the dentist, they bring fliers and ask people to vote for the project.

Currently, "Rett Research to Reality" is in sixth place, and only first and second place receive grant money. Voting can be done daily online through July 31.

"What's intense about this campaign is that it's a cumulative daily vote," Paige Nues said. "People have to be pretty committed. You don't just need a wide network, but one of people committed to put it on their Outlook to do everyday."

With help from a private foundation in Colorado called the Pioneer Fund, they are willing to match up to $1 million to help the International Rett Syndrome Foundation. If they win, the IRSF can put $500,000 towards research.

"What (the lab test) demonstration showed is that the damage done to Katie is reversible," Paige Nues said. "It's not just a cure for newly-diagnosed patients. A cure can be found; it is possible. It's not only possible for the next generation, but it's possible to help Katie today."

Source: Danville Express

Note: Click on the title to read the full original post.

First Announcement: Annual Rett syndrome Awareness Meeting/Symposium

Dear All,

As October is "Rett syndrome Awareness Month", so we are going to organize our third "Annual Rett syndrome Awareness Meet/Symposium", which is open to everybody.

Come and Join us to Raise More Global Awareness About Rett Syndrome.

Venue and Date:
Date: Sunday, October 31, 2010
Time: 10:00am - 5:00pm
Location:
Lecture Theater-II,
Second Floor, Teaching Block,
All India Institute of Medical Sciences,
Ansari Nagar, New Delhi-110029, INDIA

Please save the date in your schedules and share this with others too and make this event a success for the cause of all Rett Angels and their families. We hope to that you will give us some of your precious time for this cause by joining us and sharing it with others.

If you have any queries, feel free to contact.

Regards,

Indian Rett Syndrome Foundation
www.rettsyndromeindia.blogspot.com
E-mail: info.rett@yahoo.com

Facebook Page: http://www.facebook.com/profile.php?id=779594849#!/event.php?eid=133406410027633&index=1

Vote Pepsi Rett Research to Reality in July!

Pepsi Refresh Project

Help International Rett Syndrome Foundation Win $250K for Crucial Rett Syndrome Research Funding!
Have you voted today? IRSF is still competing to win $250K from the Pepsi Refresh Project in support of the Research to Reality Campaign for Rett syndrome research.
Today: 4th Place
Think globally, act locally & vote daily

* VOTE once a day, every day in July
o Remember: You have to sign in each time you vote (lower left hand corner)
* Sign up for Daily Email Reminders
* Visit the Research to Reality webpage under www.rettsyndrome.org->Get Involved for more information
* Add the following statement to your email signature, blog, website and/or Facebook status page
o Please Help IRSF Win $250K for Rett Syndrome Research! think globally, act locally & vote daily
Vote for Rett syndrome once per day, every day in July
- Pepsi Refresh Project!
http://www.refresheverything.com/rettresearchtoreality
*Note: Get your friends involved cut & paste this message and add to your email signature

Please note that anyone 13 years of age and over can vote! Get your teenagers and their friends voting today!

Thanks, Regards, Prayers,

Indian Rett syndrome Foundation
www.rettsyndromeindia.blogspot.com

Prolonged QT interval in Rett syndrome

By
C J Ellaway, G Sholler, H Leonard and J Christodoulou
Arch Dis Child 1999;80:470–472


Source: Pubmed

Rett syndrome, classical and atypical: genealogilcal support for common origin

By
Hans Olof Akesson, Bengt Hagberg and Jan Wahlstr6m
J Med Genet 1996;33:764-766


Source: Pubmed

Recent insights into hyperventilation from the study of Rett syndrome

By
Alison M Kerr and Peter O O Julu
Arch Dis Child 1999;80:384–387

Source: Pubmed

Rett Syndrome: Article by Dr. Angus Clarke

Very Interesting Review Article
Click on title to read it.

Source: Pubmed

Effect of Hand Splints on Stereotypic Hand Behavior of Girls with Rett Syndrome: A Replication Study

By
Helen Tuten and James Miedaner


Source: Pubmed

Hyperventilation in the awake state: potentially treatable component of Rett syndrome

D P SOUTHALL,A M KERR,E TIROSH,P AMOS,M H LANG AND J B P STEPHENSON
Archives of Disease in Childhood, 1988, 63, 1039-1048

Source: Pubmed

Selective Cerebral Volume Reduction in Rett Syndrome: A Multiple-Approach MR Imaging Study

Interesting article by

J.C. Carter, D.C. Lanham, D. Pham, G. Bibat, S. Naidu,W.E. Kaufmann

Am J Neuroradiol 29:436–41 (Mar 2008)


Source: Pubmed

Rett Syndrome The First Forty Years: 1966–2006

Interesting article by Esteller M, 2007

Click on the title to read the article.

Source: Pubmed

Oral findings in Rett syndrome: A systematic review of the dental literature

A very interesting article by

Fuertes-González MC, Silvestre FJ, Almerich-Silla JM


Please click on the title to read the same.

Source: Pubmed