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 Penn study identifies new malaria parasites in wild bonobos
21.11.2017 | University of Pennsylvania School of Medicine

nachricht NIST scientists discover how to switch liver cancer cell growth from 2-D to 3-D structures
17.11.2017 | National Institute of Standards and Technology (NIST)

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: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Researchers at IST Austria define function of an enigmatic synaptic protein

22.11.2017 | Life Sciences

Fine felted nanotubes: CAU research team develops new composite material made of carbon nanotubes

22.11.2017 | Materials Sciences

Women and lung cancer – the role of sex hormones

22.11.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>