Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

In rare disease, a familiar protein disrupts gene function

27.05.2009
Knowledge may improve diagnosis for children with Cornelia de Lange syndrome

An international team of scientists studying a rare genetic disease discovered that a bundle of proteins with the long-established function of keeping chromosomes together also plays an important role in regulating genes in humans.

When gene regulation is disrupted in the multisystem genetic disease Cornelia deLange syndrome (CdLS), children may suffer missing hands or fingers, mental retardation, growth failure, cleft palate, heart defects, and other impairments. For families and patients, better knowledge of how those genes perturb normal development may enable researchers to design better diagnostic tests for the disease, and also provide targets for eventual treatments.

The study appeared today in the online journal Public Library of Science Biology (PloS Biology). The study leader was Ian D. Krantz, M.D., a specialist in pediatric genetics at The Children's Hospital of Philadelphia, where he directs a unique full-service clinic for children with CdLS.

First described in 1933, CdLS affects multiple organs and typically results in distinctive facial features, such as thin eyebrows that join, long eyelashes, thin lips, and excessive body hair. It affects an estimated one in 10,000 children. In the past, CdLS was only recognized in its very severe form that was often fatal in childhood; now most children with the condition live into adulthood. CdLS has a wide range of severity, with the mildest form manifesting as apparent isolated mental retardation and/or autism.

Krantz and colleagues investigated cohesin, a protein complex consisting of at least four proteins that form a ring that encircles chromosomes during cell division. Cohesin's long-established role, called "canonical" by the authors, is to control chromatids—the long strands that chromosomes form when they copy their DNA.

However, said Krantz, one open question is biology has been, "What does cohesin do when cells are not dividing?" His team's paper provides part of the answer, as the first study in human cells to identify genes that are dysregulated when cohesin doesn't work properly. Cohesin's role in dysregulation of gene expression (regulating the degree to which specific genes are turned on or off) has attracted considerable scientific interest with a recent discovery that it may also be implicated in cancer.

The current study builds on previous work by Krantz, who in 2004 co-led the study that discovered NIPBL, the first gene known to cause CdLS. Krantz partnered with his long-time collaborator, Laird S. Jackson, M.D., of Drexel University School of Medicine in Philadelphia. They discovered a second CdLS gene in 2007, and together they maintain the world's largest database of patients with CdLS.

In the current study, Krantz did a genome-wide analysis of mutant cell lines from 16 patients with severe CdLS. All the cells had mutations in the NIPBL gene, which plays a role in moving cohesin onto and off chromosomes.

The researchers used DNA microarrays, manufactured chips that measure how strongly different genes are expressed throughout a cell's full complement of DNA. The study team identified hundreds of genes that were dysregulated compared to controls, and also detected gene expression profiles that were unique to CdLS. Importantly, said Krantz, the expression levels of genes corresponded to the severity of the disease. The team replicated its findings in 101 additional samples.

"We found that gene expression is exquisitely regulated by cohesin and the NIBPL gene," said Krantz. "The gene expression patterns we found have great potential to be used in a diagnostic tool for Cornelia de Lange syndrome." He added that a gene array might also be developed as a single-platform tool to diagnose, from a patient's blood sample, not only CdLS, but also a variety of other developmental disorders.

Funding for the study came from the National Institute of Child Health and Development of the National Institutes of Health, the Pennsylvania Department of Health, the Genome Network Project and Grant-in-Aid for Scientific Research from the MEXT, a Japanese government ministry. First author Jinglan Liu receives a Cornelia de Lange Foundation Fellowship Grant.

Krantz's co-authors on the study came from Children's Hospital; the University of Pennsylvania School of Medicine; Drexel University School of Medicine; the Tokyo Institute of Technology; the Misakaenosono Mutsumi Developmental, Medical, and Welfare Center, in Isahaya, Japan; and the National University of Colombia, in Bogota, Colombia.

Liu et al, "Transcriptional dysregulation in NIPBL and cohesin mutant human cells," PloS Biology, published online, May 26, 2009.

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 second in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents.

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

More articles from Health and Medicine:

nachricht A promising target for kidney fibrosis
21.04.2017 | Brigham and Women's Hospital

nachricht Stem cell transplants: activating signal paths may protect from graft-versus-host disease
20.04.2017 | Technische Universität München

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

NASA's Fermi catches gamma-ray flashes from tropical storms

25.04.2017 | Physics and Astronomy

Researchers invent process to make sustainable rubber, plastics

25.04.2017 | Materials Sciences

Transfecting cells gently – the LZH presents a GNOME prototype at the Labvolution 2017

25.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>