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 Finnish research group discovers a new immune system regulator
23.02.2018 | University of Turku

nachricht Minimising risks of transplants
22.02.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

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: Attoseconds break into atomic interior

A newly developed laser technology has enabled physicists in the Laboratory for Attosecond Physics (jointly run by LMU Munich and the Max Planck Institute of Quantum Optics) to generate attosecond bursts of high-energy photons of unprecedented intensity. This has made it possible to observe the interaction of multiple photons in a single such pulse with electrons in the inner orbital shell of an atom.

In order to observe the ultrafast electron motion in the inner shells of atoms with short light pulses, the pulses must not only be ultrashort, but very...

Im Focus: Good vibrations feel the force

A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.

By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...

Im Focus: Developing reliable quantum computers

International research team makes important step on the path to solving certification problems

Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Basque researchers turn light upside down

23.02.2018 | Physics and Astronomy

Finnish research group discovers a new immune system regulator

23.02.2018 | Health and Medicine

Attoseconds break into atomic interior

23.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>