Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mutations disrupt cellular recycling and cause a childhood genetic disease

13.08.2012
Researchers at the Children's Hospital of Philadelphia identify new gene in Cornelia deLange syndrome

Genetics researchers have identified a key gene that, when mutated, causes the rare multisystem disorder Cornelia deLange syndrome (CdLS). By revealing how mutations in the HDAC8 gene disrupt the biology of proteins that control both gene expression and cell division, the research sheds light on this disease, which causes intellectual disability, limb deformations and other disabilities resulting from impairments in early development.

"As we better understand how CdLS operates at the level of cell biology, we will be better able to define strategies for devising treatments for CdLS, and possibly for related disorders," said study leader Matthew A. Deardorff, M.D., Ph.D., a pediatric genetics clinician and scientist at The Children's Hospital of Philadelphia. Deardorff also is in the Perelman School of Medicine at the University of Pennsylvania.

Deardorff and co-corresponding author Katsuhiko Shirahige, Ph.D., of the Research Center for Epigenetic Disease at the University of Tokyo, published their study online today in Nature.

The current findings add to previous discoveries by researchers at The Children's Hospital of Philadelphia. A group led by Ian Krantz, M.D., and Laird Jackson, M.D., announced in 2004 that mutations in the NIPBL gene are the primary cause of CdLS, accounting for roughly 60 percent of the "classical" cases of the disease. In 2007, Deardorff joined them to describe mutations in two additional genes, SMC1A and SMC3. First described in 1933, CdLS affects an estimated 1 in 10,000 children.

The CdLS research team at Children's Hospital has focused on the cohesin complex, a group of proteins that form a bracelet-like structure that encircles pairs of chromosomes, called sister chromatids. "Cohesin has two roles," said Deardorff. "It keeps sister chromatids together during cell division, and it allows normal transcription—the transmission of information from DNA to RNA."

Deardorff added that mutations that perturb normal cohesin function can interfere with normal human development. Such is the case in CdLS, which exemplifies a newly recognized class of diseases called cohesinopathies.

In the current study, the scientists investigated both acetylation—how an acetyl molecule is attached to part of the cohesin complex¬—and deactylation, the removal of that molecule. Normally, deactylation helps recycle cohesin to make it available during successive rounds of cell division. The study team found that mutations in the HDAC8 gene threw off normal cellular recycling of cohesin.

Mutations in the gene cause loss of HDAC8 protein activity, and consequently decrease the amount of "recharged" cohesin available to properly regulate gene transcription. This, in turn, the researchers suggest, impairs normal embryonic development and gives rise to CdLS.

The researchers showed in cell cultures that mutations in HDAC8 lead to a decrease in cohesin binding to genes, similar to that seen for cells deficient in the NIPBL gene. They also identified HDAC8 mutations in approximately 5 percent of patients with CdLS.

Because mothers of children with CdLS may carry mutations in the HDAC8 gene, identifying these mutations will be very useful in accurately counseling families of their recurrence risk—the likelihood of having a subsequent child with CdLS.

Furthermore, added Deardorff, by providing biological details of the underlying defect in CdLS, the current research suggests future approaches to treating the genetic disease. "By concentrating downstream on the biological pathway in the cohesin cycle rather than focusing on the defective gene, we may be able to eventually screen for small-molecule drugs that could be used to intervene in CdLS."

Deardorff and colleagues will continue investigate CdLS and possible therapies. Last month, the Doris Duke Charitable Foundation chose Deardorff to receive a Clinical Scientist Development Award. This three-year award, totaling $486,000, is directed to further studies of cohesin abnormalities in human disease. Deardorff is a member of Children's Hospital's Center for Cornelia deLange Syndrome and Related Diagnoses, one of the world's leading programs in studying and treating CdLS.

Financial support for this study came from the National Institutes of Health (grants HD055488, GM49758, and HD052860), the U.S.A. Cornelia deLange Syndrome Foundation, institutional funding from The Children's Hospital of Philadelphia, intramural funding from the University of Lubeck, and the Research Program of Innovative Cell Biology by Innovative Technology. Co-authors with Deardorff and Shirahige included researchers from the United States, Japan, Canada, France, Belgium, Germany, Greece and Denmark.

"HDAC8 mutations in Cornelia deLange Syndrome affect the cohesin acetylation cycle," Nature, advance online publication Aug. 12, 2012. http://dx.doi:10.1038/nature11316

About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 516-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.

John Ascenzi | EurekAlert!
Further information:
http://www.chop.edu

More articles from Life Sciences:

nachricht Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory

nachricht Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Electron highway inside crystal

Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.

Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Researchers identify potentially druggable mutant p53 proteins that promote cancer growth

09.12.2016 | Life Sciences

Scientists produce a new roadmap for guiding development & conservation in the Amazon

09.12.2016 | Ecology, The Environment and Conservation

Satellites, airport visibility readings shed light on troops' exposure to air pollution

09.12.2016 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>