In Rare Disorder, a Familiar Protein Disrupts Gene Function

-Knowledge May Improve Diagnosis for Children with Cornelia deLange Syndrome-

PHILADELPHIA, May 27 /PRNewswire-USNewswire/ -- 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 May 26 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 in 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
received 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. For more information, visit
http://www.chop.edu.

CONTACT: John Ascenzi
267-426-6055
Ascenzi@email.chop.edu

SOURCE The Children's Hospital of Philadelphia

John Ascenzi of CHOP, +1-267-426-6055, Ascenzi@email.chop.edu