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Pathways in Cornelia de Lange Syndrome Open New Possibilities
Cornelia de Lange Syndrome (CdLS) is a relatively rare developmental diagnosis that involves a constellation of symptoms affecting almost every body system in children who have the most severe form of the diagnosis. Finding out its causes could be extremely important to understanding human development at all levels, which is why Ian Krantz, MD, medical director of the Center for Cornelia de Lange Syndrome and Related Diagnosis at The Children’s Hospital of Philadelphia, and his colleagues have dedicated the past two decades to research that is piecing together the basic biology of CdLS.
A unique aspect of the studies, which have been funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), is that it is a collaboration of scientists from across the country who started out by studying yeast and then small flies called Drosophilia, continued on to analyze zebrafish and mouse models, and then translated their findings to humans.
“This is a model of how you can go from a rare diagnosis, studying it clinically, and providing excellent care to the kids and the families, and then leveraging that population for discovery to find the genes and causes, and then to move on to the next level, which would be therapeutics, and hopefully give that back to the families,” Dr. Krantz said.
In recognition of Cornelia de Lange Syndrome Awareness Day May 9, let us take a look at the projects’ history and recent findings.
Finding the First Genetic Mutation That Causes CdLS
Most children with CdLS do not inherit the disease from their families. It results from a new change in their genetic makeup, which can be tricky to find. Using DNA sequencing technology, Dr. Krantz’s study team made an exciting discovery in 2004 when they identified the first gene, NIPBL, which causes CdLS when altered or mutated.
The gene, and the pathway it controls — called cohesin — had never been known to be mutated in any other human condition, but it is essential to cell division. Humans have 23 pairs of chromosomes that are packages of DNA, a long molecule that contains our unique genetic information. When new cells are forming, two daughter cells separate at a precise moment toward the very end of cell division and are released with duplicate copies of each chromosome.
The process that holds these duplicated chromosomes together until the end of cell division is known as sister chromatid cohesion and is regulated by cohesin, a protein complex. If it is disrupted, the chromosomes cannot go into the new cells in the right number or complement, and that is generally lethal to the cells.
Creating a ‘New Realm of Biology’
Dr. Krantz’s co-investigator, Dale Dorsett, PhD, of the department of Biochemistry and Molecular Biology at St. Louis University School of Medicine, revealed in his studies of Drosophilia that NIPBL and cohesin play another integral role in gene expression, a complicated process that involves elements in DNA called regulators that act as enhancers and repressors for target genes. Basically, these regulators communicate with a region of a gene called a promotor that tells the gene when to turn on or off, what cells to turn on or off in, and how much the gene should be turned on or off.
About 60 percent of the children with CdLS have an NIPBL mutation that the study team suggests interferes with cohesin’s role in the regulation of normal gene expression, resulting in diverse genes being turned on or off at inappropriate levels in different cells during development. For example, a child’s heart cells or brain cells may not form properly because the appropriate genes are not being told to turn on at certain levels at the right time. Since sister chromatid cohesion defects are not seen in CdLS, the investigators suggest that early dysregulation of appropriate gene expression during development is what causes the symptoms seen in children with CdLS, which include limb differences, developmental delays, autistic-like behaviors, small stature, cardiac problems, and gastrointestinal issues.
“So this is a whole new realm of biology that has been created, which is cohesin’s role in gene expression regulation and development,” Dr. Krantz said. “It has many, many roles, and it’s been one of the complexes now that is at the core of all cellular processes. It’s become a very important, very basic, fundamental biologic pathway.”
Advancing Understanding of Isolated Birth Defects
In order to further understand the basic molecular determinants of structural birth defects, the next step was to build a biological model using zebrafish and mice. Developmental biologists at the University of California Irvine, Arthur Lander, MD, PhD, and his wife, Anne Calof, PhD, had a child with CdLS who had died as a newborn. They wanted to help the researchers understand how the NIPBL gene functioned. They joined Dr. Krantz and Dr. Dorsett in successfully submitting the initial grant application to the NICHD in 2006 to leverage this information to find causes for the isolated birth defects that are seen in constellation in CdLS.
Since then, the team as achieved many discoveries, including identifying four more genes that cause CdLS when mutated all involved in the cohesin pathway. The NICHD grant was renewed in 2011, which is allowing the study team to figure out if cohesin is a master switch that regulates many genes’ expression. So far, they have found about 240 genes out of 20,000 in the human genome that are significantly up or down regulated consistently among children with CdLS. The next step is to determine if any fluctuations in those genes could disrupt downstream targets that potentially interfere with normal development.
“We could use our insight into this rare diagnosis to track down causes for much more common birth defects and intellectual disability,” Dr. Krantz said.
Translating Research Into Future Treatments
The study team is not only concentrating on identification of the causes of birth defects, but they also hope to uncover ways to treat them. Since we have two copies of all of our genes — one set inherited from our mother and one set inherited from our father — when one copy of the NIPBL gene is mutated, it results in CdLS, even though there is still another normally functioning copy. Since one mutated copy is sufficient to cause CdLS, the diagnosis follows an autosomal dominant pattern of inheritance.
The study team has shown that the normal copy of NIPBL tries to compensate for the deficient copy by increasing its level to make more normal acting NIPBL protein. If NIPBL expression levels fall below 50 percent, then the cells will likely die due to sister chromatid cohesion problems.
The study team suggests that if they can identify the regulatory mechanisms that allow the normal copy of NIPBL to somehow turn up its expression up from 50 percent to 60 or 70 percent, then perhaps they could test some drugs that could boost the gene’s expression to 80 to 90 percent and potentially help to correct some of the physiological differences seen in CdLS such as intellectual disability and slow growth.
“We’re hoping that the research will result in breakthroughs that we can then give back to the families and improve the outcomes of their children,” Dr. Krantz said.
Many families who have children with CdLS helped to establish an endowment for The Center for Cornelia de Lange Syndrome and Related Diagnoses, a “medical home” that provides multidisciplinary care for children with CdLS. Their goal is to fully fund the center with an endowment of $5 million, which will allow the Center to continue its remarkable progress in advancing novel diagnostic, management, and therapeutic tools through research.