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!
Kidney tumor: Genetic trigger discovered
18.06.2018 | Julius-Maximilians-Universität Würzburg
New type of photosynthesis discovered
18.06.2018 | Imperial College London
Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.
Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...
The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.
Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.
An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.
Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...
Light detection and control lies at the heart of many modern device applications, such as smartphone cameras. Using graphene as a light-sensitive material for...
Water molecules exist in two different forms with almost identical physical properties. For the first time, researchers have succeeded in separating the two forms to show that they can exhibit different chemical reactivities. These results were reported by researchers from the University of Basel and their colleagues in Hamburg in the scientific journal Nature Communications.
From a chemical perspective, water is a molecule in which a single oxygen atom is linked to two hydrogen atoms. It is less well known that water exists in two...
13.06.2018 | Event News
08.06.2018 | Event News
05.06.2018 | Event News
18.06.2018 | Earth Sciences
18.06.2018 | Process Engineering
18.06.2018 | Life Sciences